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Structure and function of synovial joints, with particular reference to the mechanism of their lubrication Piper, Michael Stafford 1972

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THE STRUCTURE AND FUNCTION OF SYNOVIAL JOINTS, WITH PARTICULAR REFERENCE TO THE MECHANISM OF THEIR LUBRICATION by MICHAEL STAFFORD PIPER M.D., University of B r i t i s h Columbia, 1968 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department of Anatomy We accept t h i s thesis as confirming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA JUNE, 1972 In present ing th i s thes is in pa r t i a l f u l f i lmen t of the requirements fo r an advanced degree at the Un ive rs i t y of B r i t i s h Columbia, I agree that the L ibrary sha l l make it f r ee l y ava i l ab le for reference and study. I fu r ther agree that permission for extensive copying o f th i s thes i s for s cho la r l y purposes may be granted by the Head of my Department or by his representat ives . It is understood that copying or pub l i c a t i on o f th is thes is fo r f i nanc i a l gain sha l l not be allowed without my wr i t ten permiss ion. The Un ivers i ty of B r i t i s h Colui Vancouver 8, Canada Department of ( i i ) ABSTRACT The structure and physiology of s y n o v i a l j o i n t s has been studied for years. Recent advances i n technology and i n v e s t i g a t i v e tools have enabled workers to greatly e l u c i d a t e the nature of these remarkably f u n c t i o n a l j o i n t s . This thesis presents a review of the l i t e r a t u r e dealing with the morphology and physiology of d i a r t h r o d i a l j o i n t s . The embryological development and the gross structure of these j o i n t s i s presented as i s a discussion of the l i g h t and ele c t r o n microscopic features of a r t i c u l a r c a r t i l a g e and synovial membrane. In addition, some of the features of synovial f l u i d are presented. The r e s u l t s of recent i n v e s t i g a t i o n i n t o the biochemistry and metabolism of a r t i c u l a r c a r t i l a g e are discussed. As the main function of synovial j o i n t s i s to provide pa i n l e s s , con-t r o l l e d motion, much i n t e r e s t has recently focused on the mechanism of l u b r i c a t i o n i n these j o i n t s . A review of the l i t e r a t u r e concerning the nature of j o i n t l u b r i c a t i o n i s presented, and a theory of l u b r i c a t i o n enhancement by e l e c t r i c a l r e p ulsive forces i s proposed. This theory was developed from the r e s u l t s of a technique of synovianalysis conducted on a serie s of 61 samples of syno v i a l f l u i d . The samples were c o l l e c t e d from a series of h o s p i t a l patients. One group of patients suffered from rheumatoid a r t h r i t i s , while a second group was comprised of patients s u f f e r i n g from conditions not associated with rheumatoid a r t h r i t i s . The samples were subjected to analysis using c a t i o n s e n s i t i v e glass electrodes, and the concentrations of ioni z e d sodium and potassium were measured. In addition, sodium and potassium concentrations were measured in the synovial f l u i d samples using a spectrophotometer. ( i i i ) As a r e s u l t o f t h e s e i n v e s t i g a t i o n s , i t was found t h a t the s y n o v i a l f l u i d samples from p a t i e n t s w i t h r h e u m a t o i d a r t h r i t i s c o n t a i n e d a s i g n i f i c a n t l y lower c o n c e n t r a t i o n o f i o n i z e d sodium. I t i s c o n c l u d e d t h a t the lower c o n c e n t r a t i o n o f sodium i o n s i n s y n o v i a l f l u i d o f r h e u m a t o i d a r t h r i t i s may r e s u l t i n a d i m i n u t i o n o f e l e c t r i c a l r e p u l s i v e f o r c e s a c t i n g w i t h i n s y n o v i a l j o i n t s , and e x p l a i n , i n p a r t , the c a r t i l a g e a t t r i t i o n seen i n t h i s d i s e a s e . Sydney M. Friedman P r o f e s s o r and Head Department of Anatomy U n i v e r s i t y o f B r i t i s h Columbia ( S u p e r v i s o r ) ( i v ) TABLE OF CONTENTS THE STRUCTURE AND FUNCTION OF SYNOVIAL JOINTS, WITH PARTICULAR REFERENCE TO THEIR MECHANISM OF LUBRICATION. Page No. I n t r o d u c t i o n 1 Embryology of S y n o v i a l J o i n t s 4 Gross Anatomy of S y n o v i a l J o i n t s 6 Blood and Nerve Supply of S y n o v i a l J o i n t s 8 L i g h t and E l e c t r o n Microscopy of S y n o v i a l J o i n t s 13 Sy n o v i a l Membrane and S y n o v i a l F l u i d 18 Biochemistry of A r t i c u l a r C a r t i l a g e 25 Metabolism of A r t i c u l a r C a r t i l a g e 28 L u b r i c a t i o n of S y n o v i a l J o i n t s 30 Conclusion " 37 Bi b l i o g r a p h y 39 (v) LIST OF TABLES Page No. I . Sex and Age of Experimental Sample 33 I I . Sodium and Potassium Ion Concentrations i n S y n o v i a l F l u i d of Rheumatoid and Non-Rheumatoid P a t i e n t s Measured w i t h Glass E l e c t r o d e s 34 I I I . Sodium and Potassium Concentration i n S y n o v i a l F l u i d of Rheumatoid and Non-Rheumatoid P a t i e n t s Measured w i t h the Spectrophotometer 35 IV. S y n o v i a l pH i n Rheumatoid and Non-Rheumatoid P a t i e n t s 35 V. Serum E l e c t r o l y t e s (by Flame Photometry) i n Rheumatoid and Non-Rheumatoid P a t i e n t s 36 ( v i ) ACKNOWLEDGEMENT I would l i k e t o acknowledge t h e a s s i s t a n c e g i v e n me i n t h e p r e p a r a -t i o n o f t h i s t h e s i s . I n p a r t i c u l a r I would l i k e t o thank the o r t h o p a e d i c surgeons and r a d i o l o g i s t s a t the Vancouver G e n e r a l H o s p i t a l f o r t h e i r a s s i s t a n c e i n o b t a i n i n g s y n o v i a l f l u i d samples, and Dr. G e r f r i e d G e b e r t f o r h i s t e c h n i c a l a s s i s t a n c e . I n a d d i t i o n , a p p r e c i a t i o n i s e x p r e s s e d t o Dr. Sydney M. Friedman f o r the o p p o r t u n i t y t o conduct t h i s work, and f o r h i s d i r e c t i o n and s u p p o r t . THE STRUCTURE AND FUNCTION OF SYNOVIAL JOINTS, WITH PARTICULAR REFERENCE TO THE MECHANISM OF THEIR LUBRICATION X INTRODUCTION "The F a b r i c of the J o i n t s i n the Human Body i s a Subject so much the more e n t e r t a i n i n g , as i t must s t r i k e everyone that considers i t a t t e n t i v e -l y w i t h an Idea of f i n e mechanical Composition. Where-ever the Motion of one Bone upon another i s r e q u i s i t e , there we f i n d an e x c e l l e n t Apparatus f o r r endering that Motion safe and f r e e : We see, f o r Instance, the extr e m i t y of one Bone moulded i n t o an o r b i c u l a r C a v i t y , to r e c e i v e the Head of another, i n order to a f f o r d i t an ex t e n s i v e P l a y . Both are covered w i t h a smooth e l a s t i c C rust, to prevent mutual A b r a s i o n ; connected w i t h strong Ligaments, to prevent D i s l o c a t i o n ; and enclosed i n a Bag that con-t a i n s a proper F l u i d deposited t h e r e , f o r l u b r i c a t i n g the Two contiguous S u r f a c e s . So much i n g e n e r a l . " thus wrote W i l l i a m Hunter, i n 1743 i n a remarkable essay; "Of the S t r u c t u r e and Diseases of A r t i c u l a t i n g C a r t i l a g e s ( 1 ) " . His o b s e r v a t i o n s , recorded over two hundred years ago, were extremely acute; i n f a c t , h i s d e s c r i p t i o n of the blood supply of j o i n t s , the " C i r c u l u s A r t i c u l i  Vasculosus" has p e r s i s t e d to the present time. That the s y n o v i a l j o i n t s comprised a unique body t i s s u e e a s i l y a c c e s s i b l e to i n v e s t i g a t i o n l e d e a r l y anatomists to t h e i r study. Thus, w i t h the i n t r o d u c t i o n of the microscope, the unique h i s t o l o g i c a l appear-ance of the a r t i c u l a r c a r t i l a g e s was e s t a b l i s h e d , and c a r t i l a g e was known to have a h i g h m a t r i x to c e l l r a t i o ( 2 ) . Much i n f o r m a t i o n on the nature of s y n o v i a l j o i n t s has been accumu-l a t e d i n recent y e a r s , and i t i s the purpose of t h i s paper to review - 2 -these findings. As an introduction to"these discussions I shall f i r s t review the embryology of synovial joints. One interesting aspect of this f i e l d is that of cavitation. As the limb buds develop as solid mesenchymal pro-trusions, the concept of c e l l death providing cavities at the site of joints has been developed. Teratologists have recently proposed that much pre-natal pathology results from inappropriate c e l l death and question those factors which are active in the "controlled ce l l ' death" seen i n joint formation. (3) Despite the great variation in gross structure of synovial joints, their general morphology is basically similar and these features are discussed. Recently developed injection techniques and auto-radiography have c l a r i f i e d the patterns of circulation about joints, particularly with regard to the osseous circulation, and mention of these findings and some discussion of their c l i n i c a l significance w i l l be made. (4) With regard to the fine structure of synovial joints, the introduc-tion of the electron microscope has been of great significance. The find-ings of a number of investigators are included in this discussion, as well as conclusions reached as a result of these studies. Particular reference i n this regard is made to the ultrastrueture of the synovial membrane and implications regarding the functions of the various cells within this structure. The structure of the matrix of articular cartilage has greatly limited studies as to its biochemical makeup and metabolism. However, the development of new techniques and modification of old ones has, i n the past two decades, yielded much of this information. The function of synovial joints, to paraphrase Hunter, is to provide - 3 -c o n t r o l l e d p a i n l e s s m o t i o n o f the l i m b s . To t h i s end, n a t u r e has p r o -v i d e d muscles and g r a v i t y f o r m o t i o n and l i g a m e n t s and a r c h i t e c t u r a l d e s i g n f o r s t a b i l i t y . However, i t i s the mechanism o f l u b r i c a t i o n i n s y n o v i a l j o i n t s t h a t has p r o v i d e d the g r e a t e s t i n t e r e s t as w e l l as the g r e a t e s t s o u r c e o f c o n t r o v e r s e y i n r e c e n t y e a r s . T h i s t h e s i s c o n c l u d e s w i t h a d i s c u s s i o n o f the v a r i o u s mechanisms p r o p o s e d t o a c c o u n t f o r t h i s l u b r i c a t i o n ; and, as a r e s u l t o f r e s e a r c h c o n d u c t e d t h i s y e a r , a t h e o r y o f l u b r i c a t i o n enhancement by monovalent c a t i o n s w i t h i n s y n o v i a l f l u i d . - 4 -Embryology of Synovial Joints Fore and hind limb buds appear i n the human embryo at four weeks of age as outgrowths of prim i t i v e mesenchyme. (5, 6, 7) Within a few days, a central core of mesenchyme condenses to become what i s termed the "blastema". The blastema subsequently becomes further condensed into chondrification centers, one for each s k e l e t a l element. That part of the blastema which remains following segmentation i s ca l l e d the "interzone." These are located at the si t e s of future j o i n t s , and are continuous with the perichondrium surrounding the cartilaginous models of the bones. (8) At about f i v e and one half weeks (embryo 11-17 mm) the interzone has further d i f f e r e n t i a t e d into a three layered structure with two chondro-genic layers sandwiching a loose middle layer. (9) The chondrogenic layers are continuous with the perichondrium of the neighbouring s k e l e t a l seg-ment. The intermediate layer i s continuous with the adjacent extra- > blastemal mesenchyme, which has become vascularized at this stage and i s referred to as the "synovial mesenchyme", (s i x and one h a l f weeks - 25 mm). (6, 8, 9, 10) At this stage the outer layers of the synovial mesenchyme have begun to d i f f e r e n t i a t e into the fibrous capsule, while deeper layers are d i f f e r e n t i a t i n g into synovial membrane and the i n t r a capsular structures. (9) Most authors agree that the synovial space begins to develop at about the s i x week stage of growth as minute spaces i n the synovial mesenchyme and the loose middle layer of the interzone. These small spaces subse-quently coalese to form the j o i n t cavity. (6, 8, 11, 12) However, there i s some dispute as to how cav i t a t i o n actually comes about. Some f e e l that ca v i t a t i o n i s an active process accomplished by c e l l u l a r p r o l i f e r a t i o n of. - 5 -the l i n i n g t i s s u e (9, 13). Others i n d i c a t e that c a v i t a t i o n i s the r e s u l t of c e l l death i n the i n t e r z o n e under g e n e t i c c o n t r o l . (3, 6, 14) Recent workers have suggested that i n t r a u t e r i n e movement i s e s s e n t i a l to the process of c a v i t a t i o n . (11, 12) As c a v i t a t i o n proceeds, the s y n o v i a l s urface i s at f i r s t rough and ragged, but towards the end of the embryonic p e r i o d a smooth i n t i m a l l i n i n g appears o v e r l y i n g the v a s c u l a r s u b s y n o v i a l l a y e r . By eleven weeks the j o i n t s have reached a d u l t c o n f i g u r a t i o n . - 6 -Gross Anatomy of S y n o v i a l J o i n t s A j o i n t or a r t i c u l a t i o n i s formed where two or more bones of the body meet one another. (15, 16, 17) The c h a r a c t e r and s t r u c t u r e of j o i n t s are l a r g e l y determined by t h e i r f u n c t i o n . Thus, j o i n t s may be f i b r o u s as seen i n the sutures between c r a n i a l bones, or the syndesmosis of the i n f e r i o r t i b i o f i b u l a r j o i n t . Secondly, j o i n t s may be c a r t i l a g i n o u s . Primary c a r t i l a g i n o u s j o i n t s e x i s t as the e p i p h y s e a l p l a t e between the e p i p h y s i s and d i a p h y s i s of growing bones. As such they are temporary and e v e n t u a l l y o s s i f y . Secondary c a r t i l a g i n o u s j o i n t s are seen where the a r t i c u l a r surfaces of the bones are covered w i t h h y a l i n e c a r t i l a g e and connected by a d i s c of f i b r o c a r t i l a g e . These j o i n t s a l l ow some degree of motion, and are found i n the median plane of the body - the sterno-manubrial and i n t e r v e r t e b r a l j o i n t s and the pubic symphysis. A l l other j o i n t s i n the body are r e f e r r e d to as s y n o v i a l or d i a r -t h r o d i a l j o i n t s , and have common c h a r a c t e r i s t i c s . The contiguous bony surfaces are covered w i t h a r t i c u l a r c a r t i l a g e and are not attached to one another. The a r t i c u l a r c a r t i l a g e i s u s u a l l y h y a l i n e , however, i n the case of membranous bone the a r t i c u l a r c a r t i l a g e i s white f i b r o c a r t i l a g e . The b a s a l l a y e r of the a r t i c u l a r c a r t i l a g e i s c a l c i f i e d and f i r m l y bound to the u n d e r l y i n g bone, the " a r t i c u l a r l a m e l l a . " The bones of s y n o v i a l a r t i c u l a t i o n s are bound to one another by a f i b r o u s capsule c o n s i s t i n g of a dense connective t i s s u e c u f f . G e n e r a l l y the capsule i s attached t o the bones near the periphery of the a r t i c u l a r s u r f a c e . A v a r i a b l e number of t h i c k e n i n g s i n the capsule are seen. These ligaments act to prevent excessive or abnormal movements of the j o i n t s . L i n i n g the i n n e r s u r f a c e of the f i b r o u s capsule and a t t a c h i n g to the a r t i c u l a r margins i s a s y n o v i a l membrane. This h i g h l y s p e c i a l i z e d s t r u c t u r e e n c l o s e s a p o t e n t i a l space ( t h e t r u e j o i n t space) w i t h i n w h i c h i s a s m a l l amount o f " S y n o v i a " o r " S y n o v i a l F l u i d " . The j o i n t c a v i t y may be d i v i d e d , c o m p l e t e l y or i n c o m p l e t e l y , by a f i b r o c a r t i l a g i n o u s a r t i c u l a r d i s c . These d i s c s a r e u s u a l l y a t t a c h e d t o the c a p s u l e a t t h e i r p e r i p h e r y , but a r e n o t c o v e r e d w i t h s y n o v i a l mem-bran e . S y n o v i a l j o i n t s a r e f u r t h e r c l a s s i f i e d a c c o r d i n g t o the k i n d o f m o t i o n p e r m i t t e d i n them. T h i s i s d e t e r m i n e d by the shape o f the a r t i c u l a r s u r f a c e s , the muscles t h a t a c t upon the j o i n t , and the l i m i t s p l a c e d on the j o i n t s ' e x c u r s i o n by the c a p s u l e and l i g a m e n t s . - 8 -Blood and Nerve Supply of S y n o v i a l J o i n t s I n order t o understand the blood supply to s y n o v i a l j o i n t s , one must consider two systems. The f i r s t i s the anastomotic network of v e s s e l s surrounding and s u p p l y i n g the s o f t t i s s u e s ; that i s the ligaments, capsule and synovium. The second system i s that which s u p p l i e s the e p i p h y s e a l r e g i o n and hence the subchondral bone. Ge n e r a l l y speaking the blood supply to long bones i n a p a r t i c u l a r species i s remarkably co n s t a n t . A systemic v e s s e l u s u a l l y runs p a r a l l e l to the long a x i s of the bone, and gives a n u t r i e n t a r t e r y which enters the d i a p h y s i s . T ransversely arranged v e s s e l s form anastomotic networks around the j o i n t s , and are the o r i g i n of v e s s e l s s u p p l y i n g the e p i p h y s e a l and metaphyseal r e g i o n s . The venous system tends to p a r a l l e l the a r t e r i a l system although there are u s u a l l y more veins d r a i n i n g a bone than a r t e r i e s s u p p l y i n g i t . T y p i c a l l y a s i n g l e d i a p h y s e a l a r t e r y enters the n u t r i e n t foramen and ramifys i n the marrow c a v i t y . O c c a s i o n a l l y there are two n u t r i e n t a r t e r i e s , as i n the human femur (1, 15). The epiphyses and diaphyses o f long bones are s u p p l i e d by numerous sm a l l e r n u t r i e n t a r t e r i e s . These ramify i n t o two anastomotic systems, one f o r the metaphysis and one f o r the e p i p h y s i s . These systems were o r i g i n -a l l y d escribed by Hunter. He r e f e r r e d t o the channels as "The C i r c u l u s  A r t i c u l i Vasculosias", and l i k e n e d them to the v e s s e l s of the mesentery. The metaphyseal v e s s e l s can be seen to a r i s e d i r e c t l y from the c i r c u l u s a r t i c u l i v a s c u l o s u s , w h i l e the e p i p h y s e a l v e s s e l s a r i s e from v a s c u l a r arcades l y i n g on the n o n - a r t i c u l a r p a r t of the e p i p h y s i s . (4) I t has been p o s t u l a t e d that t h i s d i f f e r e n t o r i g i n of e p i p h y s e a l and metaphyseal a r t e r i e s may account f o r the d i f f e r e n c e i n blood pressure found i n the two systems. (18) - 9 -The b lood s u p p l y of the metaphysis changes between f o e t a l and a d u l t l i f e . (19j 20, 21) I n the f o e t u s , the metaphysis i s s u p p l i e d by the n u t r i e n t a r t e r y a l o n e , w h i l e i n the a d u l t , the metaphyseal a r t e r i e s supply the p e r i p h e r a l two f i f t h s of the metaphys is , the c e n t r a l three f i f t h s s t i l l be ing s u p p l i e d by the n u t r i e n t a r t e r y . (22) This s i t u a t i o n e x i s t s i n the " g r o w i n g end" of long bones. In the " n o n - g r o w i n g end" e v e n t u a l l y a l l b l o o d d e r i v e s from the metaphyseal a r t e r i e s . L i k e w i s e there i s a change i n the b l o o d s u p p l y of e p i p h y s e s . I n the i n f a n t , (up to one y e a r ) , metaphyseal v e s s e l s p i e r c e the c a r t i l a g i n o u s e p i p h y s e a l p l a t e and thus supply the b a s a l p a r t of the e p i p h y s i s . A f t e r one y e a r of age the e p i p h y s e a l p l a t e becomes impervious t o these meta-p h y s e a l v e s s e l s , and i s s u p p l i e d s o l e l y by the e p i p h y s e a l v e s s e l s . (23) Thus i t can be seen t h a t the b l o o d supply o f the e p i p h y s e a l p a r t of long bones, and hence the subchondra l r e g i o n i s of v a r i a b l e o r i g i n , depending upon the age of the bone and the s i t e of s t u d y . This f a c t may be of r e l e v a n c e i n c o n s i d e r i n g the e t i o l o g y of a v a s c u l a r n e c r o s i s of the c a p i t a l f emora l e p i p h y s i s . (19) The r o l e of the subchondra l e p i p h y s e a l v e s s e l s i n the n u t r i t i o n of a r t i c u l a r c a r t i l a g e w i l l be d i s c u s s e d l a t e r , however, the v a s c u l a r anatomy of the e p i p h y s i s now deserves ment ion . Many e p i p h y s e a l n u t r i e n t a r t e r i e s a r i s e from the c i r c u l u s a r t i c u l i v a s c u l a s i s and anastomose w i t h i n the epiphyses of long bones. In the immature s k e l e t o n some branches pass d i r e c t l y to the s u b c h o n d r a l area of the c a r t i l a g i n o u s growth .p la te ( e p i p h y s e a l p l a t e ) , but the m a j o r i t y of the e p i p h y s e a l a r t e r i e s pass towards the a r t i c u l a r and n o n - a r t i c u l a r s u r f a c e s of the e p i p h y s i s . As these e p i p h y s e a l n u t r i e n t a r t e r i e s pass from that p a r t of the e p i p h y s i s ad jacent to the metaphysis towards the a r t i c u l a r s u r f a c e , they - 10 -feed i n t o a number of a r t e r i a l arcades which subsequently give r i s e to f u r t h e r r a d i a t i n g a r t e r i e s . (15) This p a t t e r n of the a r t e r i a l supply of the e p i p h y s i s i s s i m i l a r to the p a t t e r n of the v a s c u l a r supply seen i n the c a r t i l a g i n o u s e p i p h y s e a l p r e c u r s o r . (24) The analogy between avas-c u l a r n e c r o s i s of the femoral head i n a d u l t s (25) and that seen f o l l o w i n g r e d u c t i o n of a c o n g e n i t a l l y d i s l o c a t e d h i p (26) i s e a s i l y seen. I t has been noted that the d i s t r i b u t i o n of e p i p h y s e a l a r t e r i e s i s not r e l a t e d t o the t r a b e c u l a r a r c h i t e c t u r e of the bone. (27) The p a t t e r n of «» the trabeculae i s known to be v a r i a b l e depending upon the biomechanical forces o p e r a t i v e i n v a r i o u s c o n d i t i o n s . (28) However, the d i s t r i b u t i o n of e p i p h y s e a l a r t e r i e s appears remarkably constant. The t e r m i n a l e p i p h y s e a l a r t e r i o l e s which emanate from the anasto-motic arcades i n the c e n t r a l p a r t of the e p i p h y s i s r a d i a t e towards the subchondral bony p l a t e which supports the c a r t i l a g e . Here they form s i n u s o i d a l loops abuting against the b a s a l c a r t i l a g e l a y e r s . These are simple s i n u s o i d s not at a l l l i k e the d i l a t e d , v a r i c o s e sinuses seen on the metaphysial s i d e of the growth p l a t e . (23) O c c a s i o n a l l y these sub-chondral loops can be seen to reach i n t o the c a l c i f i e d zone of c a r t i l a g e , but only very r a r e l y i n t o the more s u p e r f i c i a l zones of u n c a l c i f i e d c a r t i l a g e . (4) The s i n u s o i d a l network i n the immediate subchondral area of the e p i p h y s i s tends to be p a r a l l e l to the a r t i c u l a r c a r t i l a g e . This v a s c u l a r anastomosis i s separated from the most b a s a l l a y e r of the c a r t i l a g e (the c a l c i f i e d zone of c a r t i l a g e ) by a t h i n p l a t e of bone. As has been men-tion e d t h i s bony p l a t e i s o c c a s i o n a l l y seen to be p e r f o r a t e d by s m a l l v a s c u l a r channels which extend i n t o the c a l c i f i e d zone of the a r t i c u l a r c a r t i l a g e . This f i n d i n g lends credence to the suggestion that the a r t i c u l a r c a r t i l a g e d e r i v e s at l e a s t p a r t of i t s n u t r i t i o n from the sub-chondral c i r c u l a t i o n . (29) The n u t r i t i o n of a r t i c u l a r c a r t i l a g e w i l l be discussed i n more d e t a i l subsequently. The veins d r a i n i n g the sinuses w i t h i n the epiphyses, although having a r a d i a t e p a t t e r n s i m i l a r to the a r t e r i e s , do not accompany the a r t e r i e s . They tend t o be more numerous than the a r t e r i e s and d r a i n to the c i r c u l u s a r t i c u l i v a s c u l o s i s . J o i n t s have a b a s i c p a t t e r n of nerve supply. The branches to them a r i s e , e i t h e r d i r e c t l y or i n d i r e c t l y , from the nerves which supply the o v e r l y i n g s k i n and the muscles which move the j o i n t . Each major a r t i c u -l a r nerve s u p p l i e s a f a i r l y l a r g e and r e l a t i v e l y constant p o r t i o n of the j o i n t . There are r e g i o n a l d i f f e r e n c e s , i n that c e r t a i n p a r t s of each j o i n t are more h e a v i l y s u p p l i e d w i t h nerve f i b e r s than are other r e g i o n s . These p a r t s are u s u a l l y those most subject to deformation during movement of the j o i n t and the grea t e r number of f i b e r s have a grea t e r c o n c e n t r a t i o n of p r o p r i o c e p t i v e endings. (30) A r t i c u l a r nerves have a common b a s i c p a t t e r n , and c o n t a i n both myelinated and non-myelinated f i b e r s . A l l myelinated f i b e r s are a f f e r e n t u s u a l l y c a r r y i n g impulses from endings of the R u f f i n i type. P a c i n i a n corpuscles are a l s o seen, u s u a l l y i n the f i b r o u s c a p s u l e . Some of the sm a l l e r a f f e r e n t myelinated f i b e r s end i n simple or f r e e nerve endings i n the capsule and are f e l t t o be simple p a i n r e c e p t o r s . Many pf the non-myelinated f i b e r s are post g a n g l i o n i c sympathetic f i b e r s s u p p l y i n g the smooth muscle of the a r t i c u l a r v e s s e l s . Some non-myelinated f i b e r s end i n free nerve endings and c a r r y a f f e r e n t p a i n impulses. The m a j o r i t y of both myelinated and non-myelinated f i b e r s are found i n the f i b r o u s capsule, .the s y n o v i a l membrane i t s e l f being very p o o r l y s u p p l i e d w i t h p a i n f i b e r s . (31) Many o f the f i b e r s i n a r t i c u l a r n e r v e s a r e vasomotor and v a s o s e n s o r y . These s u p p l y the b l o o d v e s s e l s i n the f i b r o u s c a p s u l e and s y n o v i a l mem-brane, and t h e r e b y c o n t r o l b l o o d f l o w t h r o u g h the j o i n t . The e l e v a t e d t emperature o f the o v e r l y i n g s k i n i n d i s t e n d e d p a t h o l o g i c a l j o i n t s i s e v i d e n c e o f the common s u p p l y of j o i n t s and o v e r l y i n g s k i n . (32) One c h a r a c t e r i s t i c o f the n e r v e s u p p l y t o s y n o v i a l j o i n t s i s o v e r l a p . That i s , each r e g i o n o f a j o i n t i n n e r v a t e d by one n e r v e i s s u p p l i e d by a t l e a s t one o t h e r a r t i c u l a r n e r v e . T h i s p a t t e r n o f o v e r l a p p i n g i n n e r v a t i o n may l e a d t o f a i l u r e o f p r o c e d u r e s d e s i g n e d t o d e n e r v a t e p a i n f u l a r t h r i t i c j o i n t s . - 13 -L i g h t and E l e c t r o n Microscopy of A r t i c u l a r C a r t i l a g e In r o u t i n e h i s t o l o g i c a l p r eparations of a r t i c u l a r c a r t i l a g e s chon-drocytes are seen to l i e i n lacunae d i s t r i b u t e d w i t h i n an abundant h y a l i n e i n t r a c e l l u l a r m a t r i x . (33) The chondrocytes are sparce, even i n very young c a r t i l a g e . (34, 35) E a r l y m i c r o s c o p i s t s defined four d i s t i n c t zones i n a d u l t a r t i c u l a r c a r t i l a g e , and described d i f f e r e n c e s i n the s p a t i a l arrangement as w e l l as the c e l l u l a r morphology i n these zones. (34) Zone I , the s u p e r f i c i a l or t a n g e n t i a l stratum c o n s i s t s of f l a t t e n e d or markedly ovoid c e l l s l y i n g adjacent to the sur f a c e w i t h the long a x i s of the c e l l s p a r a l l e l to the a r t i c u l a r margin. This area has a l s o been r e f e r r e d to as the " g l i d i n g zone". (36) In Zone I I , the intermediate or t r a n s i t i o n a l stratum, the chondrocytes are plump and ova l and d i s t r i b u t e d i n a random f a s h i o n . Zone I I I i s r e f e r r e d to as the deep or r a d i a t e stratum. The c e l l s i n t h i s zone tend to be sm a l l and round. They are arranged i n s h o r t , i r r e g u l a r columns p e r p e n d i c u l a r to the a r t i c u l a r s u r f a c e . The b a s a l l a y e r or Zone IV i s the c a l c i f i e d stratum, and l i e s adjacent to the subchondral bony p l a t e . I n t h i s area the c e l l s tend to be s m a l l and i r r e g u l a r w i t h p y k n o t i c n u c l e i . On hematoxylin and e o s i n s t a i n the c a l c i f i e d stratum i s separated from the more s u p e r f i c i a l l a y e r s by a t h i n wavy blue l i n e . The nature of t h i s b a s o p h i l i c area i s unknown; i t has been c a l l e d the "tidemark". F u r t h e r mention w i l l be made of the v a r i a t i o n s found i n the chondrocytes of d i f f e r -ent zones, p a r t i c u l a r l y w i t h regard to s t u d i e s w i t h the e l e c t r o n microscope. Mention should be made now, however, of the l i g h t microscopic appearance of the i n t r a c e l l u l a r m a t r i x of a r t i c u l a r c a r t i l a g e . - 14 -I t has been known f o r many years that c a r t i l a g e contains c o l l a g e n f i b e r s imbedded w i t h i n the ground substance and at l e a s t p a r t i a l l y r e s p o n s i b l e f o r the s t i f f n e s s of the m a t r i x . (37) Benninghoff, i n 1925, suggested that c o l l a g e n formed bundles arranged i n arcades. He f e l t t h a t these bundles were anchored i n the c a l c i f i e d stratum and ran v e r t i c a l l y towards the surface through the r a d i a t e stratum. At the t r a n s i t i o n a l zone the f i b e r s turned o b l i q u e l y to f o l l o w the t a n g e n t i a l o r i e n t a t i o n of the s u p e r f i c i a l l a y e r . They then turned down, running p e r p e n d i c u l a r l y back through the r a d i a l zone to become anchored again i n the c a l c i f i e d zone. These "Benninghoff arcades" can be demonstrated usi n g phase c o n t r a s t microscopy. (30) However, recent e l e c t r o n m i c r o s c o p i c s t u d i e s have i n d i -cated a f a r more random o r i e n t a t i o n of the f i b e r s . The e l e c t r o n microscope has r e c e n t l y been used e x t e n s i v e l y i n an attempt t o c l a r i f y the nature of a r t i c u l a r c a r t i l a g e . These s t u d i e s have shed l i g h t on the o r g a n i z a t i o n of the e x t r a c e l l u l a r m a t r i x , as w e l l as i n d i c a t i n g the source of the components of the m a t r i x . In a d d i t i o n , s t u d i e s w i t h the scanning e l e c t r o n microscope have c o n t r i b u t e d to a g r e a t e r understanding of the nature of the surface of the " g l i d i n g c a r t i l a g e s " . E a r l y s t u d i e s w i t h the e l e c t r o n microscope (39) i n d i c a t e d a v a r i a t i o n i n the s i z e of the f i b e r s found w i t h i n the m a t r i x , and subsequent work has confirmed t h i s . (40, 41, 42, 43) I n t r a c e l l u l a r d i f f e r e n c e s are a l s o noted i n the s p e c i f i c zones of the c a r t i l a g e . E l e c t r o n micrographs of the s u p e r f i c i a l or t a n g e n t i a l stratum show i t to extend to a depth of 200 to 600 m i c r a , being t h i c k e r at the periphery of the c a r t i l a g e where i t blends w i t h the perichondrium. The s u r f a c e of the c a r t i l a g e i s covered w i t h a l a y e r of f i n e f i b e r s and f i l a m e n t s about three micra i n depth. Scanning e l e c t r o n micrographs of t h i s s urface l a y e r - 15 -have l e d some i n v e s t i g a t o r s t o b e l i e v e t h a t i t c o r r e s p o n d s t o a l a y e r o f adsorbed h y a l u r o n i c a c i d . (44) B i o c h e m i c a l s t u d i e s have c o r r o b o r a t e d t h i s c o n c e p t . (45) L i g h t m i c r o s c o p i s t s r e f e r r e d t o t h i s s u p e r f i c i a l l a y e r as the " l a m i n a s p l e n d e n s " . (46) The f i b r o u s elements o f the remainder o f Zone I ( t a n g e n t i a l s t r a t a ) show the t y p i c a l c o l l a g e n p e r i o d i c i t y of 64 OX. They have a d i a m e t e r o f about 35 OA and a r e a r r a n g e d i n bundles r u n n i n g p a r a l l e l t o the a r t i c u l a r s u r f a c e s a t o b l i q u e o r r i g h t a n g l e s t o one a n o t h e r . These i n d i v i d u a l f i b e r s a r e t i g h t l y packed w i t h r e l a t i v e l y l i t t l e i n t e r v e n i n g m a t r i x as compared t o the deeper l a y e r s . I n the narrow zones o f m a t r i x s u r r o u n d i n g the c e l l s o f t h i s r e g i o n f i n e f i b e r s 12OA i n d i a m e t e r w i t h a p e r i o d i c i t y o f 100X a r e s e e n r u n n i n g between c o l l a g e n - b u n d l e s . There a r e a l s o a number o f f i n e f i l a m e n t o u s f i b r i l s o f 40A* d i a m e t e r and a c h a r a c t e r i s t i c beaded appearance. The s m a l l e l l i p s o i d c h o n d r o c y t e s of Zone I d i f f e r markedly from those o f the deeper l a y e r s . They have a r e l a t i v e l y p o o r l y d e v e l o p e d rough endo-p l a s m i c r e t i c u l u m , the m i t o c h o n d r i a a r e s m a l l , and the G o l g i a p p a r a t u s forms f l a t t e n e d sacs a p p a r e n t l y d e v o i d o f m a t e r i a l . (47) A number o f s e c r e t o r y v a c u o l e s a r e seen c o n t a i n i n g m a t e r i a l s i m i l a r i n appearance t o the f i l a m e n t o u s f i b r i l s o f the e x t r a c e l l u l a r m a t r i x . (41) 0 I n Zone I I , ( t h e t r a n s i t i o n a l s t r a t u m ) c l a s s i c c o l l a g e n f i b e r s w i t h a p e r i o d i c i t y o f 64 OA* and a d i a m e t e r r a n g i n g from 300 t o 600A" a r e seen. These f i b e r s a r e randomly a r r a n g e d and have l e s s tendency t o form bundles t h a n t h o s e s e e n i n the s u p e r f i c i a l zone. The amorphous ground s u b s t a n c e i s more abundant, and a g a i n the f i n e f i b e r s and f i l a m e n t o u s f i b r i l s a r e seen. The l a r g e r c h o n d r o c y t e s i n t h i s zone have a s c a l l o p e d appearance t o t h e i r c e l l membrane n o t seen i n Zone I. I t i s s u g g e s t e d t h a t t h i s a p pear-ance r e s u l t s from l a r g e v e s i c l e s merging w i t h the c e l l w a l l t o d i s c h a r g e - 16 -t h e i r c o n t e n t s . (41) There i s a l a r g e q u a n t i t y o f w e l l d e v e l o p e d rough endoplasmic r e t i c u l u m , as w e l l as a w e l l d e v e l o p e d G o l g i complex w i t h many v e s i c l e s . I n a d d i t i o n a l a r g e number o f m i t o c h o n d r i a a r e seen. These f i n d i n g s i n d i c a t e t o most workers t h a t t h e s e c e l l s a r e a c t i v e l y p r o d u c i n g p r o t e i n , p a r t i c u l a r l y c o l l a g e n . (37, 38, 42, 47) The e l e c t r o n m i c r o s c o p i c p i c t u r e of Zone I I I , the r a d i a t e s t r a t a , i s v e r y s i m i l a r t o t h a t o f Zone I I . A g a i n the c o l l a g e n f i b e r s have a c h a r a c t e r i s t i c p e r i o d i c i t y o f 640A\ but they tend t o be s l i g h t l y l a r g e r i n d i a m e t e r (400A1 t o 800S). T h e i r arrangement a g a i n i s random (41) a l t h o u g h some o b s e r v e r s s t a t e t h a t i n u l t r a - t h i n s e c t i o n s t h e r e appears to be a preponderance o f f i b e r s r u n n i n g p e r p e n d i c u l a r to t h e c a r t i l a g e s u r f a c e . (47) The c h o n d r o c y t e s o f t h i s zone are s i m i l a r t o t h o se of Zone I I w i t h s l i g h t l y l e s s e x t e n s i v e o r g a n e l l e s . The dense c a l c i u m d e p o s i t s i n the c a r t i l a g e m a t r i x of"Zone IV h i n d e r t h e p r e p a r a t i o n of good s e c t i o n s f o r e l e c t r o n m i c r o s c o p y . I n the depths o f the c a l c i f i e d zone, many of the c h o n d r o c y t e s appear d e g e n e r a t e or n e c r o t i c , and a r e s u r r o u n d e d by c a l c i f i e d m a t r i x . The c a l c i f i e d w a l l i s , however, s e p a r a t e d from the c e l l w a l l by a narrow zone o f u n c a l c i f i e d m a t r i x . The c a l c i f i e d m a t r i x has a homogenous e l e c t r o n - d e n s e appearance. As mentioned above, a number o f the c e l l s appear n e c r o t i c . However, t h e h e a l t h y c e l l s resemble those of Zone I I I ; t h a t i s they have the c h a r a c t e r -i s t i c o r g a n e l l e s of c e l l s i n v o l v e d i n p r o t e i n s y n t h e s i s . (47) I n 1743, i t was s u g g e s t e d t h a t c a r t i l a g e was a n e u r a l and a v a s c u l a r (1), and t h i s has been c o n f i r m e d i n r e c e n t t i m e s . (48) C a r t i l a g e c h a n n e l s have been d e s c r i b e d i n immature a n i m a l s but t h e s e a r e f e l t not t o c o n t r i b -u t e t o the nourishment o f the c h o n d r o c y t e s . They d i s a p p e a r e a r l y i n l i f e . (4) - 17 -The n u t r i t i o n of a r t i c u l a r c a r t i l a g e w i l l be discussed l a t e r , however one f u r t h e r note as to the dynamics of the chondrocyte should be made at t h i s time. Although m i t o t i c f i g u r e s have been described i n the c a r t i l a g e of immature animals they are not seen i n normal a r t i c u l a r c a r t i l a g e from mature animals. (41, 42, 47, 49) M i t o t i c f i g u r e s are o c c a s i o n a l l y seen under c o n d i t i o n s of l a c e r a t i v e i n j u r y (42) or compression.(50) In o l d e r animals c a r t i l a g e c e l l s w i t h i r r e g u l a r shaped n u c l e i are o c c a s i o n a l l y seen, and were once thought to represent a m i t o t i c d i v i s i o n . In recent years s t u d i e s w i t h t r i t i a t e d thymidine, (an i n d i c a t o r of DNA r e p l i c a t i o n ) have shown tha t a zone of chondrocyte p r o l i f e r a t i o n e x i s t s adjacent to the zone of c a l c i f i c a t i o n u n t i l the onset of m a t u r i t y . (51) These f i n d i n g s would tend to i n d i c a t e that the c e l l count of a r t i c u -l a r c a r t i l a g e would d i m i n i s h w i t h a g i n g . This seems to be true i n the case of r a b b i t s and c a t t l e , but st u d i e s w i t h human a r t i c u l a r c a r t i l a g e have f a i l e d to show a s i m i l a r f a l l i n c e l l count. (35) In view of the f r e -quency of c e l l death seen on e l e c t r o n microscopic s t u d i e s , these f i n d i n g s are as yet unexplained. - 18 -S y n o v i a l Membrane and S y n o v i a l F l u i d The unique nature of d i a r t h r o d i a l j o i n t s i s a f u n c t i o n of both the h y a l i n e c a r t i l a g e found at the a r t i c u l a t i n g ends of bones, and the s y n o v i a l membrane. Normal s y n o v i a l membrane can be thought of as con-s i s t i n g of two p a r t s : a t h i n i n ner l i n i n g bounding the j o i n t space and r e f e r r e d to as the s y n o v i a l i n t i m a , and a s u p p o r t i v e l a y e r r e f e r r e d to as the subintima or su b s y n o v i a l t i s s u e . As discussed i n the embryology of j o i n t s , the s y n o v i a l membrane i s der i v e d from the embryonic mesenchyme of the o r i g i n a l s k e l e t a l blastema (5 2 ) . The r e g e n e r a t i o n of s y n o v i a l membrane f o l l o w i n g t o t a l synovectomy i n d i c a t e s t h a t i t i s r e a l l y a modified form of mesothelium. (53) The f u n c t i o n of s y n o v i a l membrane i s f e l t t o be t w o - f o l d . C e r t a i n c e l l s appear to have a phagocytic f u n c t i o n and the s t r u c t u r e i s a l s o r e s p o n s i b l e f o r the pr o d u c t i o n of s y n o v i a l f l u i d . (54) These phenomena w i l l be discussed more f u l l y . G r o s s l y the s y n o v i a l membrane can be seen to l i n e the inner s u r f a c e of d i a r t h r o d i a l j o i n t s . I t i s attached to the margins of the a r t i c u l a r c a r t i l a g e s , and the subintima blends w i t h the i n t r a - a r t i c u l a r periosteum. The membrane o f t e n may be redundant and thrown i n t o f o l d s or v i l l i . The blood supply of the s y n o v i a l membrane, as w e l l as that of the f i b r o u s capsule, d e r i v e s from the c i r c u l u s a r t i c u l i v a s c u l o s i s . G e n e r a l l y speaking there i s an a r t e r i a l network l y i n g j u s t beneath the subintima as i t blends w i t h the contiguous periosteum. This gives r i s e to a r t e r i a l ' arcades which pass through the s y n o v i a l membrane and appear to branch i n t o c a p i l l a r y beds at the j u n c t i o n between i n t i m a and subinti m a . (55, 4) Under the l i g h t microscope s y n o v i a l membrane can be c l a s s i f i e d on the ba s i s of the predominant s t r u c t u r e of the s u b i n t i m a l connective t i s s u e . Thus, depending upon the site of origin of the synovium i t may be fibrous, fibro-areolar, areolar, areolar-adipose or adipose. (33, 55) The synovial intima has a characteristic appearance composed of a layer of cells varying in depth from one to four imbedded in a matrix of ground substance. The intimal cells have frequent branching cell processes with a finely granular cytoplasm which extend to the surface of the synovial membrane and to other cells. One of the characteristic features of the synovial intimal cells is that although they are more numerous on the surface of the synovial membrane, they do not form a continuous unbroken layer as on an endothelial surface. (55, 56) The intimal cells are generally ellipsoid in shape with an oval nucleus. The synovial intima lies on a meshwork of subintimal connective tissue, with numerous capillaries just below the lining surface. (57) The sub-intimal portion of the synovial membrane also has a characteristic cell population. About three percent of the subintimal cells are mast cells, and tend to occupy the region between the intima and subintima. Also within the subintima is a collection of unclassified connective tissue cells, predominantly fibroblasts. (56) Collagen fibers provide the major structural support for the subintima, and, to a lesser degree, the intima. Electron microscopy has contributed greatly to the study of the synovial membrane, both with regard to the nature and function of the synovial cells, and to the relationship between the cells and the surrounding matrix.. The light microscopic impression that synovial cells did not form a complete lining of the joint cavity has been confirmed by electron microscopy. (47, 58) Thus the subintima is not exposed to the joint space, although intimal cells and their surrounding matrix are bathed in synovial fluid. Also noticeable is the absence of a basement membrane in synovial membrane. - 20 -The nature of the s y n o v i a l i n t i m a l c e l l s has been g r e a t l y e l u c i d a t e d w i t h the e l e c t r o n microscope. Two types have been d i s t i n g u i s h e d ; types A and B c e l l s ; the A c e l l s being more frequent. (58) The fundamental mor-p h o l o g i c a l d i s t i n c t i o n between the two types of c e l l s i n that type A c e l l s c o n t a i n prominent G o l g i complexes and many smooth w a l l e d v a c u o l e s , but l i t t l e rough endoplasmic r e t i c u l u m , w h i l e type B c e l l s are r i g h l y endowed w i t h endoplasmic r e t i c u l u m , but G o l g i systems and smooth w a l l e d vacuoles are scanty. Despite the f a c t that type A c e l l s are more frequent than type B, and d e s p i t e t h e i r morphological d i f f e r e n c e s , most authors tend to agree th a t the d i f f e r e n t types do not represent d i s t i n c t populations of c e l l s , but r a t h e r v a r i a n t s whose morphology i s dependent upon f u n c t i o n a l a c t i v i t y . This concept i s supported by the f a c t that intermediate c e l l types w e l l endowed w i t h both rough endoplasmic r e t i c u l u m and G o l g i complexes are found. A l s o , i n some p a t h o l o g i c a l c o n d i t i o n s there may be a p r o l i f e r a t i o n of one c e l l type over another. (47) The f i n d i n g of two types of c e l l s i n s y n o v i a l i n t i m a has l e d t o a g r e a t e r i n s i g h t i n t o the f u n c t i o n of the membrane, and much i n t e r e s t has centered around the p r o d u c t i o n of s y n o v i a l f l u i d . Of p a r t i c u l a r i n t e r e s t i s the source of s y n o v i a l mucin or h y a l u r o n i c a c i d . This i s a s u l f a t e -f r e e mucopolysaccharide c o n t a i n i n g equimolar concentrations of g l u c u r o n i c a c i d and N-acetyIglucosamine. (54, 56) This c o i l e d macromolecule i s r e s p o n s i b l e f o r the v i s c o u s nature of s y n o v i a l f l u i d , and c o n t r i b u t e s , at l e a s t p a r t i a l l y , to j o i n t l u b r i c a t i o n . S y n o v i a l membrane has been shown to produce hyaluronate i n v i t r o and i n v i v o . (54, 59) Using c o l l o i d a l i r o n techniques w i t h e l e c t r o n microscopy, i t has been shown that h y a l u r o n i c a c i d i s produced i n the G o l g i complex and t r a n s p o r t e d to the m a t r i x and the j o i n t c a v i t y by the l a r g e smooth w a l l e d v a c u o l e s . I t seems s i n c e the G o l g i complex and smooth w a l l e d vacuoles are the c h a r a c t e r i s t i c f eatures of type A c e l l s , i t i s these c e l l s which are mainly r e s p o n s i b l e f o r h y a l u r o n i c a c i d s y n t h e s i s . (60) I n a d d i t i o n to the p r o d u c t i o n of h y a l u r o n i c a c i d , the type A c e l l s are a c t i v e i n removing substances from the s y n o v i a l f l u i d . These c e l l s are a c t i v e i n phagocytosing both small p a r t i c u l a t e matter, and a l s o l a r g e r objects such as c e l l fragments and e r y t h r o c y t e s . (61) The f i n d i n g of l a r g e amounts of rough endoplasmic r e t i c u l u m i n the l e s s frequent type B c e l l s has i n d i c a t e d t h a t these c e l l s are a c t i v e l y engaged i n the manufacture of p r o t e i n . Although almost a l l the p r o t e i n found i n s y n o v i a l f l u i d i s f e l t t o d e r i v e from the plasma, two percent of t h i s p r o t e i n i s found i n the s y n o v i a l f l u i d f i r m l y bound to h y a l u r o n i c a c i d . (56, 62) I t has been suggested t h a t t h i s s m a l l f r a c t i o n ' o f s y n o v i a l f l u i d p r o t e i n may a r i s e from the s m a l l p o p u l a t i o n of type B c e l l s . (47, 58) The m a t r i x of the s y n o v i a l i n t i m a has a mottled appearance, w i t h v a r y i n g e l e c t r o n d e n s i t y . Collagen w i t h c h a r a c t e r i s t i c 640^ p e r i o d i c i t y i s seen, as w e l l as very f i n e f i b r i l l a r y f i b e r s . I n areas of synovium where the i n t i m a l c e l l s are three to f o u r deep, a rough d i v i s i o n between s u p e r f i c i a l , middle and deep zones can be made. G e n e r a l l y speaking, i t i s i n the deep zone that most of the banded c o l l a g e n i s found, w h i l e the f i n e r f i b e r s are seen i n the more s u p e r f i c i a l zones w i t h the g r a n u l a r amorphous m a t r i x . (47, 58) The e l e c t r o n m i c r o s c o p i c appearance of the s u b s y n o v i a l t i s s u e or sub-i n t i m a depends l a r g e l y upon the nature of the area ( i . e . f i b r o u s , a r e o l a r or a d i p o s e ) . I n a l l v a r i e t i e s , f i b r o b l a s t s , mast c e l l s and t i s s u e macro-phages are found. One c h a r a c t e r i s t i c f e a t u r e of the subintima i s i t s h i g h v a s c u l a r i t y , w i t h many a r t e r i o l e s and c a p i l l a r i e s . The c a p i l l a r i e s extend - 22 -i n t o the i n t i m a , and i n f a c t may be separated from the j o i n t space by only a t h i n band of i n t i m a l m a t r i x . (47) There i s a v a r i a b l e amount of banded c o l l a g e n p r o v i d i n g the framework of the s u b i n t i m a . Any d i s c u s s i o n of the s y n o v i a l membrane must i n c l u d e a c o n s i d e r a t i o n of s y n o v i a l f l u i d . The term "synovia" was f i r s t used by Paracelsus i n the 16th century, who l i k e n e d i t s appearance to egg w h i t e . (56, 62) S y n o v i a l f l u i d has been de f i n e d as "a p r o t e i n c o n t a i n i n g d i a l y s a t e of blood plasma, to which mucin, s e c r e t e d by the s y n o v i a l c e l l s , i s added as the plasma water d i f f u s e s through the s y n o v i a l t i s s u e spaces i n t o the l a r g e r t i s s u e space, the j o i n t c a v i t y " . (62) Grossly, s y n o v i a l f l u i d i s c l e a r , pale y e l l o w , v i s c i d , and does not c l o t . I t i s weakly a l k a l i n e , w i t h a pH of from 7.39 to 7.8. (63) The c h a r a c t e r i s t i c v i s c o s i t y of s y n o v i a l f l u i d i s provided by h y a l -u r o n i c a c i d , a s u l f a t e - f r e e mucopolysaccharide. This i s a long chained polymerized molecule of equimolar p r o p o r t i o n s of g l u c u r o n i c a c i d and N-acetylglucosamine having a molecular weight of about one m i l l i o n . H y a l u r o n i c a c i d content i n normal s y n o v i a l f l u i d i s approximately 3.6 m i l l i -grams per gram. (17) Various f u n c t i o n s f o r h y a l u r o n i c a c i d i n s y n o v i a l f l u i d have been p r o -posed. I t i s o p e r a t i v e i n m a i n t a i n i n g l u b r i c a t i o n i n j o i n t s . This can be seen when hyaluronidase i s i n t r o d u c e d i n t o a j o i n t and r a p i d breakdown of a r t i c u l a r c a r t i l a g e r e s u l t s . (64, 65) I t has a l s o been suggested' t h a t the hyaluronate a c i d may i n some way m a i n t a i n the water balance w i t h i n the j o i n t . (56) Normal s y n o v i a l f l u i d contains about one t h i r d the p r o t e i n found i n serum (2.5 grams per 100 m i l l i l i t r e s ) , w i t h a h i g h e r a l b u m i n - g l o b u l i n r a t i o . Albumin forms 75 percent of the p r o t e i n . The percentage of alpha - 23 -and beta g l o b u l i n i s s i m i l a r to that found i n serum, w h i l e the percentage of alpha-2 g l o b u l i n and gamma g l o b u l i n i s l e s s . Furthermore, a l l serum p r o t e i n s w i t h a molecular weight i n excess of 160,000 are excluded from s y n o v i a l j o i n t s . Of p a r t i c u l a r importance i s the absence of f i b r i n o g e n , prothrombin, thrombin, and t h r o m b o p l a s t i n . These large molecular weight p r o t e i n s are excluded from j o i n t s by the p r e f e r e n t i a l p e r m e a b i l i t y of the c a p i l l a r y membrane and the ground substance of the s y n o v i a l membrane. (17) Thus s y n o v i a l f l u i d w i l l not c l o t . S y n o v i a l f l u i d normally contains a s m a l l c e l l u l a r component, ranging up t o 200 w h i t e c e l l s per m i l l i l i t r e . The m a j o r i t y of the nucleated c e l l s w i t h i n s y n o v i a l f l u i d are phagocytes, w i t h monocytes being the most p r e -v a l e n t . The normal low p o p u l a t i o n of polymorphonuclear leukocytes (about 2 percent) leads to the s u s p i c i o n of i n f e c t i o n when any higher l e v e l i s found. (66) Red blood c e l l s are very r a r e i n normal f l u i d and are f e l t to r e s u l t from trauma. Inorganic m a t e r i a l s such as non-protein n i t r o g e n and glucose tend t o r e f l e c t serum l e v e l s , both being s l i g h t l y lower i n s y n o v i a l f l u i d . S i m i l a r -l y , e l e c t r o l y t e s tend t o be s l i g h t l y lower i n s y n o v i a l f l u i d than the serum, (62) and a f u r t h e r d i s c u s s i o n of the c o n c e n t r a t i o n s of sodium and potassium w i l l f o l l o w . A number of enzymes have been found i n s y n o v i a l f l u i d , and c o n s i d e r a b l e e f f o r t i s p r e s e n t l y being expended i n an attempt to c o r r e l a t e abnormal enzyme l e v e l s w i t h a r t i c u l a r c a r t i l a g e damage i n v a r i o u s j o i n t d i s e a s e s . A number of dehydrogenases, transaminases and phosphotases have been measured i n s y n o v i a l f l u i d , however t h e i r l e v e l of a c t i v i t y seems to c o r -r e l a t e w i t h the number of leukocytes found i n the s y n o v i a l f l u i d . One of the features of s y n o v i a l f l u i d i s i t s tendency to accumulate - 24 -as a result of pathology. Synovianalysis is a great aid i n diagnosing various forms of a r t h r i t i s and i n assessing the efficacy of treatment. (66) - 25 -B i o c h e m i s t r y o f A r t i c u l a r C a r t i l a g e F u n c t i o n b e i n g so c l o s e l y r e l a t e d t o s t r u c t u r e , much e f f o r t has r e c e n t l y been expended i n t o c l a r i f y i n g the b i o c h e m i c a l n a t u r e o f c a r t i l a g e . In a d d i t i o n , new t e c h n i q u e s have e n a b l e d r e s e a r c h e r s t o d e t e r m i n e the m e t a b o l i s m o f the c h o n d r o c y t e , i n s p i t e o f l i m i t a t i o n s imposed by the h i g h m a t r i x t o c e l l r a t i o . The l i g h t and e l e c t r o n m i c r o s c o p i c c h a r a c t e r i s t i c s o f the i n t r a c e l l u -l a r m a t r i x have been d e s c r i b e d . B i o c h e m i c a l l y , one o f the most i n t e r e s t -i n g f e a t u r e s o f c a r t i l a g e i s i t s h y p e r h y d r a t e d s t a t e , the w a t e r c o n t e n t m e a s u r i n g up t o 80%. ( 6 7 , 6 8 ) Much o f t h i s w a t e r i s no t t i g h t l y bound , (as i n bone , a l a r g e p r o p o r t i o n o f the w a t e r c o n t e n t b e i n g bound to the m i n e r a l c r y s t a l ) bu t i s f e l t t o fo rm a g e l i n c o m b i n a t i o n w i t h the muco-p o l y s a c c h a r i d e s . I t has been s u g g e s t e d t h a t the e l a s t i c b e h a v i o u r o f a r t i c u l a r c a r t i l a g e i s l a r g e l y dependent upon the w a t e r c o n t e n t . ( 6 9 ) Over 5 0 7 o o f the d r y w e i g h t o f a r t i c u l a r c a r t i l a g e and 9 0 7 , o f the p r o -t e i n c o n t e n t i s c o l l a g e n . The amino a c i d c o m p o s i t i o n appea r s to be i d e n -t i c a l w i t h t h a t o f o t h e r c o l l a g e n s , a l t h o u g h t h e r e may be a s l i g h t l y i n c r e a s e d q u a n t i t y o f h y d r o x y l y s i n e . ( 7 0 ) I t has p r o v e d e x t r e m e l y d i f f i -c u l t t o s e p a r a t e t he c o l l a g e n o f a r t i c u l a r c a r t i l a g e f r om the p r o t e i n p o l y -s a c c h a r i d e . T h i s appea rs t o be due t o a complex i n t e r a c t i o n between the m u c o p o l y s a c c h a r i d e s i d e c h a i n s o f c h o n d r o i t i n s u l f a t e s and c o l l a g e n f i b r i l s . ( 7 1 ) The p r o t e i n p o l y s a c c h a r i d e s make up the m a j o r i t y o f the r e s t o f the o r g a n i c component o f a r t i c u l a r c a r t i l a g e s . These complexes a r e h i g h m o l e c u l a r w e i g h t m a c r o m o l e c u l e s , c o n s i s t i n g o f a p r o t e i n c o r e t o w h i c h i s a t t a c h e d a number o f s i d e c h a i n s o f s u l f a t e d p o l y s a c c h a r i d e s . A l t h o u g h the p r o t e i n c o r e v a r i e s c o n s i d e r a b l y i n s i z e and amino a c i d c o n t e n t , the i - 26 -b a s i c u n i t i s thought to be about 4000S 1 ong w i t h about 60 p o l y s a c c h a r i d e s i d e c h a i n s . (72, 73) The p o l y s a c c h a r i d e s i d e chains are composed of repeated dimeric "glycosaminoglycan" (GAG) u n i t s . Three of these dimeric u n i t s have been described i n a r t i c u l a r c a r t i l a g e ; c h o n d r o i t i n - 4 s u l f a t e , c h o n d r o i t i n - 6 s u l f a t e , and k e r a t i n s u l f a t e . (73) The number of saccharide u n i t s i n a macromolecule may range between 50 and 50,000. The p r o t e i n polysaccharides are not d i f f u s e l y d i s t r i b u t e d throughout c a r t i l a g e , but are found i n highest c o n c e n t r a t i o n immediately surrounding the c e l l s . (74) In a d d i t i o n the three glycosaminoglycans are d i f f e r e n t l y d i s t r i b u t e d w i t h i n the c a r t i l a g e . As mentioned i n the d i s c u s s i o n of the u l t r a s t r u c t u r e of c a r t i l a g e , the c o n c e n t r a t i o n of c e l l p r o t e i n p o l y s a c c h a r -ides i s markedly decreased i n the s u p e r f i c i a l or g l i d i n g s t r a t a . (40) K e r a t i n s u l f a t e i s found p r i m a r i l y i n the i n t e r t e r r i t o r i a l regions ( t h a t i s between the v a r i o u s s t r a t a ) . Otherwise, k e r a t i n s u l f a t e i s i n low concentrations but may be found to i n c r e a s e w i t h o l d age. Chondroitin-6 s u l f a t e i s the most prevalent of the three glycosaminogens found i n a r t i c u l a r c a r t i l a g e , w i t h c h o n d r o i t i n - 4 s u l f a t e having a h i g h c o n c e n t r a t i o n i n the embryonic p e r i o d but decreasing w i t h advancing age. (75) The p r o t e i n polysaccharides are f e l t to be important i n p r o v i d i n g much of the r e s i l i e n c y of a r t i c u l a r c a r t i l a g e - perhaps by m a i n t a i n i n g the s p a t i a l o r i e n t a t i o n of the c o l l a g e n f i b e r s . Some other organic m a t e r i a l s are found i n s m a l l q u a n t i t i e s i n a r t i c -u l a r c a r t i l a g e . S i a l i c a c i d , probably i n the form of s i a l o p r o t e i n , l i k e l y e x i s t s i n combination w i t h the p r o t e i n p o l y s a c c h a r i d e complexes. (76) In a d d i t i o n there are low concentrations of l i p i d s found w i t h i n the matrix of c a r t i l a g e . (77) The nature and f u n c t i o n of t h i s m a t e r i a l i s unknown. A l s o , a number o f enzymes have been found w i t h i n the a r t i c u l a r c a r t i l a g e s ; t h e s e w i l l be d i s c u s s e d under the m e t a b o l i s m o f c a r t i l a g e . W i t h r e g a r d t o t h e i n o r g a n i c components o f a r t i c u l a r c a r t i l a g e , the c o n c e n t r a t i o n o f e l e c t r o l y t e s i s s i m i l a r t o t h a t found i n o t h e r i n t r a -c e l l u l a r f l u i d s (68, 78), w i t h two e x c e p t i o n s . F i r s t , the c o n c e n t r a t i o n o f bound and unbound s u l f a t e s a r e v e r y h i g h , ( u n d e r s t a n d a b l y i n view o f the c o n c e n t r a t i o n o f s u l f a t e d p o l y s a c c h a r i d e s ) . A l s o , t h e r e i s an i n c r e a s e i n the c o n c e n t r a t i o n o f sodium, w h i c h s e r v e s as t h e p r i n c i p a l c a t i o n f o r the p o l y a n i o n i c m a t r i x . - 28 -Metabolism of A r t i c u l a r C a r t i l a g e U n t i l f a i r l y r e c e n t l y , measurements of r e s p i r a t o r y a c t i v i t y had i n -d i c a t e d that a r t i c u l a r c a r t i l a g e had a very low metabolic a c t i v i t y . How-ever, subsequent s t u d i e s pointed out the very low c e l l mass of c a r t i l a g e , and suggested that the r a t e of metabolic a c t i v i t y per c e l l approached that of other t i s s u e s . Most of the g l y c o l y t i c enzymes have been demonstrated i n a r t i c u l a r c a r t i l a g e , and i n a d d i t i o n , c a r t i l a g e has been shown t o be only m i n i m a l l y a f f e c t e d by periods of oxygen d e p r i v a t i o n . In a d d i t i o n , l a c t i c a c i d has been found i n h i g h c o n c e n t r a t i o n i n the t i s s u e . These f i n d i n g s have suggested that the metabolic a c t i v i t y of c a r t i l a g e i s c o n s i s -tent w i t h i t s avascular c h a r a c t e r , and that the anaerobic pathway i s w e l l developed. (79) In a d d i t i o n , e a r l y i n v e s t i g a t o r s a l s o thought that the chondrocytes were " i n e r t " and at m a t u r i t y , had l i t t l e s y n t h e t i c a c t i v i t y . However, subsequent i n v e s t i g a t i o n s u t i l i z i n g r a d i o s u l f a t e uptake showed a r a p i d r a t e of turnover f o r at l e a s t the s u l f a t e d p o l y s a c c h a r i d e component of the m a t r i x . (80) I t appears now that the chondrocytes are i n v o l v e d i n a " c o n t i n u a l complex p a t t e r n of a c t i v i t y d i r e c t e d e n t i r e l y (or almost e n t i r e l y ) to s y n t h e s i s , maintenance and degradation of the macromolecules that compose the i n t r a c e l l u l a r m a t e r i a l " . (81) I t has been shown that the chondrocyte i s capable of the s y n t h e s i s of the p r o t e i n of both the p r o t e i n p o l y s a c c h a r i d e and c o l l a g e n , the s y n t h e s i s of the p o l y s a c c h a r i d e (and i t s p o l y m e r i z a t i o n ) , and the s u l f a t i o n of the p o l y s a c c h a r i d e . (82, 83) Much of the q u a l i t a t i v e and q u a n t i t a t i v e i n f o r m a t i o n on the metabolic a c t i v i t y of a r t i c u l a r c a r t i l a g e has been d e r i v e d from the use of i s o t o p i c t r a c e r s s p e c i f i c to the macromolecules s y n t h e s i z e d . Thus both synthesis and degradation r a t e s can be determined. From these s t u d i e s a number of con-- 29 -e l u s i o n s have been reached. The r a t e of s y n t h e s i s of the macromolecules has been found to be more r a p i d i n immature animals but a f t e r an i n i t i a l d e c l i n e remains f a i r l y constant throughout l i f e . (49) A number of a n t i m e t a b o l i t e s can be seen t o i n h i b i t t h i s s y n t h e s i s . I n a d d i t i o n , the net s y n t h e s i s of macromolocules has been shown to i n c r e a s e immediately f o l l o w i n g l a c e r a t i v e i n j u r y t o a r t i c u l a r c a r t i l a g e . A l s o , there i s an i n c r e a s e i n s y n t h e s i s i n o s t e o a r t h r i t i c j o i n t s . (84) Normal c a r t i l a g e shows no net g a i n i n m a t r i x volume, d e s p i t e the h i g h r a t e of s y n t h e s i s of i t s c o n s t i t u e n t macromolecules. R e c e n t l y , a degrada-t i v e system has been described capable of s p l i t t i n g the p r o t e i n p o l y -saccharide at or near the s u g a r - p r o t e i n band s i t e . One such protease has been r e f e r r e d to as "cathepsin-D", a lysosomal enzyme found both i n t r a and e x t r a c e l l u l a r l y . (85, 86) I t has been proposed that the c a p a c i t y of both r a t e s of s y n t h e s i s and degradation suggests the presence of an a c t i v e i n t e r n a l r e m o d e l l i n g system. (81, 86). That the chondrocytes of a r t i c u l a r c a r t i l a g e are m e t a b o l i c a l l y a c t i v e r a t h e r than i n e r t has become obvious. However, controversy s t i l l e x i s t s as to the source of n u t r i t i v e m a t e r i a l s f o r t h i s a c t i v i t y . Most e a r l y i n v e s t i g a t o r s , n o t i n g the a v a s c u l a r i t y of the t i s s u e , suggested t h a t the s y n o v i a l f l u i d was the only source of n u t r i t i o n f o r c a r t i l a g e . Although mi c r o v a s c u l a r channels have been demonstrated p e r f o r a t i n g the bony p l a t e and e n t e r i n g the p o o r l y c a l c i f i e d b a s a l zone of immature c a r t i l a g e these channels cannot be i d e n t i f i e d i n mature animals. (40, 87) Most curr e n t i n v e s t i g a t o r s f e e l t h a t n u t r i t i v e m a t e r i a l s d i f f u s e through the m a t r i x from the s y n o v i a l f l u i d b a t h ing the c a r t i l a g e s u r f a c e . - 30 -L u b r i c a t i o n of S y n o v i a l J o i n t s As Hunter noted i n 1743, the prime f u n c t i o n of s y n o v i a l j o i n t s i s to "render motion safe and f r e e " and that t h i s f u n c t i o n was accomplished by a "bag that contains a proper f l u i d deposited there f o r l u b r i c a t i n g the two contiguous s u r f a c e s " . (1) This p a r t i c u l a r l y f r i c t i o n - f r e e movement, found to have a c o e f f i c i e n t of f r i c t i o n of about 0.013, (88) has f a s c i n a t e d both engineers and b i o l o g i s t s f o r y e a r s , and the source of t h i s extremely e f f i c i e n t l u b r i c a t i o n i s s t i l l h i g h l y c o n t r o v e r s i a l . The h i g h l y viscous nature of s y n o v i a l f l u i d has been noted, and has been f e l t t o add g r e a t l y to the l u b r i c a t i o n of s y n o v i a l j o i n t s . (89, 90) A number of t h e o r i e s have been proposed i n an attempt to e x p l a i n the phenomenon of j o i n t l u b r i c a t i o n . "Hydrodynamic l u b r i c a t i o n " was suggested when the i n c o n g r u i t y of j o i n t surfaces was noted. (91) In t h i s system, two r i g i d surfaces s et at an angle to one another were seen to produce a wedge-shaped gap. When one sur f a c e moves t a n g e n t i a l l y to the other the viscous s y n o v i a l f l u i d i s drawn i n t o the d i m i n i s h i n g gap, and a pressure i s developed w i t h i n the f l u i d s u f f i c i e n t t o support the v e r t i c a l l o a d . This proposal was att a c k e d on the b a s i s that hydrodynamic l u b r i c a t i o n i s not s u i t e d to r e c i p r o c a t i n g movement, as seen i n p h y s i o l o g i c a l c o n d i t i o n s . (88) A l s o , the hig h pressures to which a r t i c u l a t i n g j o i n t s are subjected to i n normal weight bearing l e d to the development of the theory of "boundary l u b r i c a t i o n " as a p p l i e d to s y n o v i a l j o i n t s . I n t h i s model, the l u b r i c a n t ( f o r example the hyaluronate of s y n o v i a l f l u i d ) has an a f f i n i t y f o r the s o l i d s u r f a c e s . Movement takes place between mono-molecular l a y e r s of adherent l u b r i c a n t . (88) This model i s t h e o r e t i c a l l y a t t r a c t i v e , how-ever i n v i t r o experiments have found t h i s form of l u b r i c a t i o n a c t i n g at only very l i g h t l o a d s . (92) • - 31 -The theory of "weeping l u b r i c a t i o n " r e l a t e d the n u t r i t i o n of c a r t i l a g e to the l u b r i c a t i o n mechanism. (93) The porous nature of a r t i c u l a r c a r t i l -age enables i t to take up l u b r i c a t i n g f l u i d ; w i t h the a p p l i c a t i o n of a load the f l u i d i s squeezed out and provides a f l u i d f i l m f o r l u b r i c a t i o n . (93, 94) Most i n v e s t i g a t o r s f e e l that "elastohydrodynamic l u b r i c a t i o n " i s a c t i v e i n periods of r a p i d motion w i t h l i g h t l oads, as i n the swing phase of w a l k i n g . (92, 95, 96) This m o d i f i c a t i o n of the hydrodynamic theory developed when i t was seen that forces w i t h i n s y n o v i a l j o i n t s could produce an e l a s t i c deformation of the c a r t i l a g e . This deformation can be seen t o generate a t h i c k e r wedge of l u b r i c a t i n g f l u i d . (95) As mentioned i n the d i s c u s s i o n of the u l t r a s t r u c t u r e of a r t i c u l a r c a r t i l a g e , scanning e l e c t r o n micrographs have shown the s u r f a c e of these c a r t i l a g e s to be r e l a t i v e l y rough. (97) Thus has developed the combined theory of "boosted l u b r i c a t i o n " f o r a r t i c u l a r c a r t i l a g e s . (92, 97) This theory suggests t h a t as pressure i s a p p l i e d across a j o i n t , opposing peaks of c a r t i l a g e meet, and between these peaks boundary l u b r i c a t i o n i s a c t i v e . Pools of s y n o v i a l f l u i d accumulate i n the depressions between the peaks. As the pressure r i s e s , water and other low molecular weight substances d i f f u s e between the pores of the c a r t i l a g e and c o l l e c t i o n s of v i s c o u s , hyaluronate r i c h f l u i d are generated. (94) This h i g h l y v i s c o u s f l u i d p r o -vides a modified f l u i d f i l m f o r f u r t h e r l u b r i c a t i o n . (92) A recent study measured the thickness of s y n o v i a l f l u i d f i l m s from he a l t h y and a r t h r i t i c j o i n t s . I t was noted that both f l u i d f i l m s decreased i n thickness w i t h the a p p l i c a t i o n of lo a d , but that the a r t h r i t i c f l u i d f i l m was always c o n s i d e r a b l y l e s s . Furthermore, the thickness of the f l u i d f i l m from diseased j o i n t s could be made to approach that of normal f l u i d - 32 -by the a d d i t i o n of sodium c h l o r i d e . The d i f f e r e n c e i n the thic k n e s s of the f l u i d f i l m s was f e l t t o be due t o a d i f f e r e n c e i n the number of e l e c t r i c a l r e p u l s i v e forces adsorbed onto n e g a t i v e l y charged surface molecules. (98) To date the only recorded measurements of s y n o v i a l f l u i d e l e c t r o l y t e s are those which have been obtained using flame photometry. (62, 66) These values correspond to the t o t a l c o n c e n t r a t i o n of the e l e c t r o l y t e i n q u e s t i o n . However, recent advances i n the use of c a t i o n s e n s i t i v e g l a s s e l e c t r o d e s have enabled i n v e s t i g a t o r s to measure the i o n i z e d f r a c t i o n of v a r i o u s e l e c t r o l y t e s i n b i o l o g i c a l f l u i d s . (99, 100) I t has been suggested t h a t the c a t i o n i c f r a c t i o n of these e l e c t r o l y t e s represent t h e i r b i o l o g i c a l l y a c t i v e p a r t (99), and i t was e l e c t e d t o s u b j e c t s y n o v i a l f l u i d samples to such an a n a l y s i s . I t was f e l t t h a t i f a r t h r i t i c f l u i d had less b i o l o g i c a l l y a c t i v e forces t h i s might account f o r the breakdown of l u b r i c a t i o n found i n a r t h r i t i c j o i n t s . Method Sixty-one samples of s y n o v i a l f l u i d were obtained at arthrotomy or by a s p i r a t i o n , and these were d i v i d e d i n t o 2 groups. Eleven p a t i e n t s had rheumatoid a r t h r i t i s . The remaining f i f t y s u f f e r e d from c o n d i t i o n s not a s s o c i a t e d w i t h rheumatoid a r t h r i t i s ; the m a j o r i t y having arthrotomy of the knee f o r i n t e r n a l derangement or f o r m i n i s c a l t e a r s . The mean age of the rheumatoid group was 48.7, and there was a predominance of females. In the non-rheumatoid group, the mean age was 35.4 and there were more males. - 33 -TABLE I - Sex and Age of Experimental Sample Rheumatoid Group 11 ( 7 female, 4 male) Mean Age 48.7 Non-Rheumatoid Group 50 (15 female, 35 male) Mean Age 35.4 T o t a l 61 The samples were analyzed f o r i o n i z e d sodium and potassium u s i n g flow-through e l e c t r o d e s connected i n s e r i e s and s h i e l d e d i n a metal box. The r e s u l t i n g e l e c t r o d e p o t e n t i a l s were read on two V i b r o n Electrometers which were c a l i b r a t e d d a i l y u s i n g weighed standards. The samples were subjected t o f u r t h e r a n a l y s i s u s i n g the Techtron Atomic A d s o r p t i o n Spectrophotometer and, when volume p e r m i t t e d , the pH of the sample was determined. The mean c o n c e n t r a t i o n of sodium ions i n the rheumatoid group was 139.0 m E q / l i t r e . This was compared to a mean of 148.9 m E q / l i t r e i n the non-rheumatoid group. There was l i t t l e d i f f e r e n c e i n the potassium i o n concentrations i n the two groups, the mean l e v e l s being 2.52 m E q / l i t r e and 2.57 m E q / l i t r e r e s p e c t i v e l y . R e s u l t s - 34 -TABLE I I - Sodium and Potassium Ion Concentrations i n S y n o v i a l F l u i d of Rheumatoid and Non-Rheumatoid P a t i e n t s Measured w i t h Glass E l e c t r o d e s . [Na +] Rheumatoid Group 139.0 mEq/1 (Range 135 mEq/1 - 146 mEq/1) (Standard D e v i a t i o n 3.16 mEq/1) Non-Rheumatoid Group 148.9 mEq/1 (Range 141 mEq/1 - 154 mEq/1) (Standard D e v i a t i o n 3.31 mEq/1) [ K + ] Rheumatoid Group 2.52 mEq/1 (Range 1.6 mEq/1 - 2.8 mEq/1) (Standard D e v i a t i o n 0.41 mEq/1) Non Rheumatoid Group 2.57 mEq/1 (Range 1.8 mEq/1 - 3.0 mEq/1) (Standard D e v i a t i o n 0.49 mEq/1) When the samples were subjected t o a n a l y s i s using the spectrophoto-meter, a s i m i l a r trend was noted. The rheumatoid group had a mean concen-t r a t i o n of 130.7 m E q / l i t r e compared to 135.7 m E q / l i t r e i n the non-rheumatoid group, w h i l e potassium c o n c e n t r a t i o n s were 4.3 m E q / l i t r e and 4.7 m E q / l i t r e . The lower concentrations of sodium seen using the s p e c t r o -photometer were f e l t to be due t o both the h i g h p r o t e i n content of the f l u i d , and t o a d i l u t i o n a l phenomenon. - 35 -TABLE I I I Sodium and P o t a s s i u m C o n c e n t r a t i o n s i n S y n o v i a l F l u i d o f Rheumatoid and Non-Rheumatoid P a t i e n t s Measured w i t h the Sp e c t r o p h o t o m e t e r [Na] Rheumatoid Group 130.7 mEq/1 Non-Rheumatoid Group 135.7 mEq/1 [K] Rheumatoid Group 4.3 mEq/1 (Range 128 mEq/1 - 136 mEq/1) ( S t a n d a r d D e v i a t i o n 4.5 mEq/1) (Range 120 mEq/1 - 142 mEq/1) ( S t a n d a r d D e v i a t i o n 5.4 mEq/1) (Range 3.9 mEq/1 - 4.7 mEq/1) ( S t a n d a r d D e v i a t i o n 0.33 mEq/1) Non-Rheumatoid Group 4.7 mEq/1 (Range 3.4 mEq/1 - 6.5 mEq/1) ( S t a n d a r d D e v i a t i o n 0.55 mEq/1) An a n a l y s i s o f the s y n o v i a l f l u i d pH showed the rh e u m a t o i d group t o have a c o n s i s t e n t l y lower pH than the second group, the mean l e v e l s b e i n g 7.10 and 7.42 r e s p e c t i v e l y . TABLE IV S y n o v i a l pH i n Rheumatoid and Non-Rheumatoid P a t i e n t s Rheumatoid Group Non-Rheumatoid Group pH 7.10 mEq/1 7.42 mEq/1 Range (6.9 mEq/1 - 7.3 mEq/1) (7.25 mEq/1 - 7.53 mEq/1) - 36 -The q u e s t i o n a r o s e as t o whether the d i f f e r e n c e i n s y n o v i a l e l e c t r o -l y t e s r e f l e c t e d d i f f e r e n c e s i n serum c o n c e n t r a t i o n s . Serum e l e c t r o l y t e d e t e r m i n a t i o n s were a v a i l a b l e i n a number o f p a t i e n t s , and showed no c o r r e l a t i o n w i t h the l e v e l s found i n s y n o v i a l f l u i d . TABLE V Serum E l e c t r o l y t e s (By Flame Photometry) i n Rheumatoid and Non-Rheumatoid P a t i e n t s . [Na] [K] Rheumatoid Group (Mean) 139 mEq/1 (Mean) 4.3 mEq/1 Non-Rheumatoid Group (Mean) 140 mEq/1 (Mean) 4.4 mEq/1 A l l o f the above r e s u l t s were s u b j e c t e d t o s t a t i s t i c a l a n a l y s i s . The d i f f e r e n c e i n the two groups i n g l a s s e l e c t r o d e d e t e r m i n a t i o n s o f s y n o v i a l f l u i d sodium was found t o be h i g h l y s i g n i f i c a n t . (p<0.0001) D i s c u s s i o n T h i s paper r e p r e s e n t s an a ttempt t o e x p l a i n one o f the p o s s i b l e mechanisms o f the c a r t i l a g e wear s e e n i n r h e u m a t o i d a r t h r i t i s . That a number o f l u b r i c a t i o n mechanisms a r e a c t i v e i n s y n o v i a l j o i n t s has be-come o b v i o u s i n r e c e n t y e a r s . (101) F l u i d f i l m s and boundary l u b r i c a t i o n b o t h appear t o be a c t i v e i n d i f f e r e n t phases o f j o i n t movement. When i t was found t h a t the t h i c k n e s s o f f l u i d f i l m s from a r t h r i t i c j o i n t s was c o n s i d e r a b l y l e s s t h a n t h o s e o f normal s y n o v i a l f l u i d , i t was s u g g e s t e d t h a t e l e c t r i c a l r e p u l s i v e f o r c e s were r e s p o n s i b l e f o r the maintenance of t h e s e f l u i d f i l m s . T h i s was s u b s t a n t i a t e d by the f a c t t h a t t h e a r t h r i t i c f l u i d f i l m s c o u l d be made t o a p p roach the t h i c k n e s s o f normal f l u i d f i l m s by t h e a d d i t i o n of e l e c t r o l y t e s o l u t i o n s . (98) - 36a -T h i s s t u d y has shown t h a t the c o n c e n t r a t i o n o f i o n i z e d sodium i s s i g n i f i c a n t l y l e s s i n s y n o v i a l f l u i d samples from r h e u m a t o i d a r t h r i t i c s , as compared t o samples from non-rheumatoid p a t i e n t s . T h i s d i f f e r e n c e may be due t o the h i g h e r c o n c e n t r a t i o n o f p r o t e i n found i n r h e u m a t o i d j o i n t s , w h i c h may b i n d f r e e sodium i o n s . (66) The lower c o n c e n t r a t i o n o f i o n i z e d sodium w i l l r e s u l t i n a d e c r e a s e i n the e l e c t r i c a l r e p u l s i v e f o r c e s a c t i n g w i t h i n a j o i n t , and subsequent-l y a d i m i n u t i o n i n the f l u i d f i l m t h i c k n e s s . Thus, a breakdown i n l u b r i c a t i o n as a r e s u l t o f t h i n n e d f l u i d f i l m s r e s u l t s . T h i s may e x p l a i n , i n p a r t , t h e c a r t i l a g e a t t r i t i o n s e e n i n a r t h r i t i c j o i n t s . - 37 -CONCLUSION Advances i n the knowledge of s y n o v i a l j o i n t anatomy and physiology have p a r a l l e l e d s i m i l a r advances i n other b i o l o g i c a l f i e l d s . Although the s y n o v i a l membrane has, i n the past , a t t r a c t e d the gr e a t e s t a t t e n t i o n w i t h regard t o the pathogenesis of j o i n t d i s e a s e , new i n t e r e s t i s now being focused on a l t e r a t i o n s i n a r t i c u l a r c a r t i l a g e . As i t i s on c a r t i l a g e i n t e g r i t y that u s e f u l j o i n t f u n c t i o n depends, a breakdown i n t h i s i n t e g r i t y , e i t h e r m echanically or b i o c h e m i c a l l y , r e s u l t s i n l o s s of f u n c t i o n . Loss of f u n c t i o n i n only one o f the many s y n o v i a l j o i n t s of the body can r e s u l t i n great l i m i t a t i o n of an i n d i v i d u a l ' s c a p a c i t y . Thus a grea t e r understanding of the u l t r a s t r u c t u r e and metabolism of s y n o v i a l j o i n t s and the changes tha t occur w i t h the i n t r o d u c t i o n of pathology, i s le a d i n g b a s i c s c i e n t i s t s and c l i n i c i a n s c l o s e r t o an understanding of the pathogenesis of the va r i o u s a r t h r i t i d i e s . The complexity of these f i n d i n g s i s r e f l e c t e d by the recent l i t e r a t u r e d e a l i n g w i t h the pathogenesis of rheumatoid a r t h r i t i s . (102, 103) This paper i s an attempt to review the s t r u c t u r e and f u n c t i o n of normal s y n o v i a l j o i n t s , w i t h p a r t i c u l a r reference t o the u l t r a s t r u c t u r a l aspects of t h e i r anatomy. In a d d i t i o n , a review of the c u r r e n t concepts of j o i n t l u b r i c a t i o n i s i n c l u d e d , and a theory of di s o r d e r e d l u b r i c a t i o n , d e r i v e d from the r e s u l t s of experimental work conducted on s y n o v i a l f l u i d , i s presented. Research continues i n many r e l a t e d f i e l d s , i n c l u d i n g r e i m p l a n t a t i o n of p r o s t h e t i c j o i n t s (104, 105), and the use of a r t i f i c i a l l u b r i c a n t s . (106) I t i s , however, through a gr e a t e r understanding of the ba s i c r e l a -t i o n s h i p between the s t r u c t u r e and metabolism of b i o l o g i c a l t i s s u e s and t h e i r u l t i m a t e f u n c t i o n that answers to many unanswered questions w i l l be found. - 38 -Hunter d e s c r i b e d the penultimate r e s u l t of a diseased j o i n t i n 1743, and concluded: "at l a s t the unhappy Person must submit to E x t i r p a t i o n , a d o u b t f u l Remedy, or wear out a p a i n f u l , though probably a s h o r t L i f e . " (1) His concern was as ap p r o p r i a t e at that time as i t would be today. - 39 -BIBLIOGRAPHY General 1. HUNTER, W., Of the S t r u c t u r e and Diseases of A r t i c u l a t i n g C a r t i l a g e s , P h i l . Trans. R. Soc. 42:514 (1743). 2. LEIDY, J . , On the Intimate S t r u c t u r e and H i s t o r y of A r t i c u l a r C a r t i l a g e . Amer. J . Med. Science 17:277 (1849). . 3. 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