Br J Ophthalmol: first published as 10.1136/bjo.60.3.161 on 1 March 1976. Downloaded from Brit. J. Ophthal. (I976) 6o, i6i

Editorial: The importance of being

The eye, by its specialized structure and accessi- thiocyanate (NaCNS) results in the 'unmasking' of bility to examination, provides a unique window for considerable collagenolytic activity. These circu- the study of connective tissues when they are lating inhibitors would therefore seem to be part involved in systemic disease processes. The severest of the homoeostatic control mechanism to prevent forms of ocular complications-for example, kera- excessive activity in chronic inflam- tolysis and necrotizing scleritis-underline the vital matory states. In addition, inactive pre- role which collagen plays in the basic architecture cursors or procollagenases have been found in of the eye and emphasize the importance of the the culture media of bone explants in vitro (although study of control mechanisms for its biosynthesis and the possibility that this is an inactive enzyme- biodegradation, and their perturbation by patho- inhibitor complex has not been entirely excluded). logical processes. In these experiments 'unmasking' of the latent At present the process of extracellular fibre collagenase activity was achieved after incubation formation is the subject of active investigation. with a variety of enzymic substances-for example, Recent studies (Olsen and Prockop, I974) have trypsin, lysosomal extracts, cathepsin BI, Kallikrein, demonstrated the mobilization of previously syn- and plasmin (Vaes and Eeckhout, I975). Many of thesized procollagen within Golgi vesicles which these substances could well be expected to operate in are then transported to the plasma membrane by an inflammatory lesion, although these authors feel the microtubular system. After fusion of the that other proactivators may further complicate the Golgi vesicle with the plasma membrane the system. Collagenase activity may also respond to procollagen molecules are released into the extra- different controls in various organs. The collagenase cellular space where the non-helical polypeptide production of involuting uterine explants has been extensions are cleaved by a procollagen peptidase. shown to be markedly inhibited by progesterone, This allows normal fibre bundle formation and especially when augmented by dibutyryl cyclic cross linking of the molecules to occur (Lapiere adenosine monophosphate (AMP). Similar inhibitory and Pierard, 1974). Deficient activity of this effects of the cyclic nucleotide and theophylline http://bjo.bmj.com/ enzyme is responsible for dermatosparaxis in the (a cyclic phosphodiesterase inhibitor) were also calf. In this hereditary disorder of connective found in human skin cultures but progesterone was tissue, procollagen forms the fibrous framework inactive in this system (Jeffery, Koob, and Eisen, (Tenaers, Ansay, Nusgens, and Lapiere, I971), 1975); the same workers also showed that the skin and the dermal connective tissue is very fragile collagenase production was inhibited by extremely (Hanset and Ansay, I967). Collagen synthesis can low levels of cortisol and dexamethasone which also influenced were effective on rheumatoid be by the similarly synovia. on October 1, 2021 by guest. Protected copyright. itself (Nevo and Dorfman, 1972), and this control The recent demonstration of collagenase activity may be sufficiently sensitive to order the type of associated with corneal fibroblasts (Hook, Hook, collagen synthesized (Slavkin, Croissant, and and Brown, I973) is obviously of particular in- Guenther, 1975). In developing tissues the distri- terest. When the control mechanisms for this bution patterns of collagen fibre width play an enzyme have been fully studied, the pathogenesis important role in morphogenesis (Robert and of a suddenly developing keratolysis or sclero- Robert, 1975), and in the embryonic eye, physical malacia perforans will undoubtedly be better factors-such as, developing intraocular pressure- understood, and it is not too much to hope that may operate to produce the highly structured collagenase inhibitors other than corticosteroids orthogonal lattice of collagen fibres in the cornea, will be found, and will prove to be effective and so produce a regular conformational response. in the control of such connective-tissue destruction The control of collagen biodegradation in vivo is without concomitantly slowing down the rate of less well understood at present, because of the reparative synthesis. many factors which seem to be involved. Circulating Finally, one must consider how the foregoing inhibitors of collagenase activity have been reported outline of the underlying 'mechanics' can be in serum, an M2 macroglobulin and a, antitrypsin modified by substances derived from the patho- (Eisen, Bloch, and Sakai, I970), and an a2 macro- logical lesions themselves. In this respect the globulin-enzyme complex in synovial fluids from granulomatous lesions of the sclera are of prime patients with rheumatoid arthritis (Abe and Nagai, importance, as by definition they represent a I973). Dissociation of this complex in sodium failure of biodegradation and characteristically Br J Ophthalmol: first published as 10.1136/bjo.60.3.161 on 1 March 1976. Downloaded from x62 British Journal of Ophthalmology

are a source of numerous acid . In this hydrolases (Henson, 1971; Weissman, Zurier, connexion, ingested inert particles by rabbit Spieler, and Goldstein, I97i). There are thus synovial fibroblasts have been shown to secrete many other possibilities for collagenase production increased quantities of a collagenase (Werb and and/or activation from products secreted by cells Burleigh, 1974) and a neutral proteinase (Werb involved in the granuloma. and Reynolds, 1974). Neutral proteinases are of The interrelations between immunopathological special importance by their action upon proteogly- stimuli, connective-tissue enzymology and homoeo- can core , the dissolution of which enables stasis, in the ocular complications of rheumatoid further enzyme access. The ingestion of antigen/ arthritis and other connective-tissue diseases, will antibody complexes by cells have also been shown undoubtedly provide a very exciting field of to result in the extracellular release of lysosomal ophthalmological investigation in the future.

References ABE, S., and NAGAI, Y. (I973) 7. Biochem. (Tokyo), 73, 897 EISEN, A. Z., BLOCH, K. j., and SAKAI, T. (1970) 7. Lab. clin. Med., 75, 258 HANSET, R., and ANSAY, M. (I967) Ann. Mid. vit., 7, 45I HENSON, P. M. (I971) J7. exp. Med., 134, I I4S HOOK, R. M., HOOK, C. W., and BROWN, S. I. (1973) Invest. Ophthal., 12, 771 JEFFERY, J. J., KOOB, T. j., and EISEN, A. Z. (1975) In 'Dynamics of Connective Tissue Macromolecules', eds P. M. C. Burleigh and A. R. Poole, p. 147. Elsevier North-Holland Excerpta Medica, Amsterdam LAPIERE, CH. M., and PIERARD, G. (1974) J. invest. Derm., 62, 582 NEVO, Z., and DORFMAN, A. (1972) Proc. nat. Acad. Sci. (Wash.), 69, 2069 OLSEN, B. R., and PROCKOP, D. J. (1974) Ibid., 71, 2033 ROBERT, B., and ROBERT, L. (1975) Protides Biol. Fluids, 22, 15 SLAVKIN, H. C., CROISSANT, R. D., and GUENTHER, H. (I975) Ibid., 22, 23 TENAERS, A., ANSAY, M., NUSGENS, B., and LAPIERE, CH. M. (197I) Europ. 7. Biochem., 23, 533 VAES, G., and EECKHOUT, Y. (I975) In 'Dynamics of Connective Tissue Macromolecules', eds P. M. C. Burleigh, and A. R. Poole, p. 129. Elsevier North-Holland Excerpta Medica, Amsterdam WEISSMAN, G., ZURIER, R. B., SPIELER, P. J., and GOLDSTEIN, I. M. (1971) Y. exp. Med., 134, 149S WERB, Z., and BURLEIGH, P. M. C. (1974) Biochem. Y., 137, 373 , and REYNOLDS, J. J. (I974) J. exp. Med., x40, 1482 http://bjo.bmj.com/ on October 1, 2021 by guest. Protected copyright.