Abstract
There are similarities between the actions of estrogen and relaxin on the connective tissues of the pubic symphysis and those of neutral proteases on cartilage in osteoarthritis, including cartilage hydration, proteoglycan loss, and dissolution of collagen fibers.
We hypothesized that compounds known to inhibit cartilage breakdown in animal models of osteoarthritis, such as polysulfated GAGs, would also antagonize the actions of estrogen and relaxin that increase the laxity and mobility of the pubic symphyses of guinea pigs.
Estrogen-primed guinea pigs were injected with relaxin or with relaxin and the test compound. The pubic symphyses were manually palpated 6 h later and the degree of mobility scored. Glycosaminoglycan polysulfates and pentosan polysulfate inhibited relaxin-induced pubic symphyseal relaxation, whereas other types of agents were without effect.
The guinea pig pubic symphysis assay for relaxin may thus provide a novel rapid screening test for compounds with potential chondroprotective activity.
Similar content being viewed by others
References
L. C. Miller and C. A. Dinarello,Biologic activities of interleukin-1 relevant to rheumatic diseases. Pathol. Immunopathol. Res.6, 22–36 (1987).
H. B. Fell and R. W. Jubb,The effect of synovial tissue on the breakdown of articular cartilage in organ cultures. Arth. Rheum.20, 1359–1371 (1977).
K. Desmukh-Phadke, M. Lawrence and S. Nanda,Synthesis of collagenase and neutral proteases by articular chondrocytes: Stimulation by a macrophage-derived factor. Biochem. Biophys. Res. Commun.85, 490–496 (1978).
T. Krakauer, J. J. Oppenheim and H. E. Jasin,Human interleukin-1 mediates cartilage matrix degradation. Cell Immunol.91, 92–99 (1985).
J. Saklatvala, S. J. Sarsfield and L. M. C. Pilsworth,Characterization of proteins from human synovium and mononuclear leukocytes that induce resorption of cartilage proteoglycan in vitro. Biochem. J.209, 337–344 (1983).
E. M. O'Byrne, H. C. Schroder, C. Stefano and R. L. Goldberg,Catabolin/interleukin-1 regulation of cartilage and chondrocyte metabolism. Agents and Actions21, 341–344 (1987).
J. T. Dingle, D. P. Page Thomas, B. King and D. R. Bard,In vivo studies of articular cartilage damage mediated by catabolin/interleukin-1. Ann. Rheum. Dis.46, 527–533 (1987).
E. C. Arner, T. M. DiMeo, D. M. Ruhl and M. A. Pratta,In vivo studies on the effects of human recombinant interleukin-1β on articular cartilage. Agents and Actions27, 254–257 (1989).
E. M. O'Byrne, V. Blancuzzi, D. E. Wilson, M. Wong and A. Y. Jeng,Blevated substance P and accelerated cartilage degradation in rabbit knees injected with interleukin-1 and tumor necrosis factor. Arth. Rheum.33, 1023–1028 (1990).
A. A. J. van de Loo and W. B. van den Berg,Effects of murine recombinant interleukin-1 on synovial joints in mice: Measurement of patellar cartilage metabolism and joint inflammation. Ann. Rheum. Dis.49, 238–245 (1990).
J. Steinberg, S. Tsukamoto and C. B. Sledge,A tissue culture model of cartilage breakdown in rheumatoid arthritis. III. Effects of antirheumatic drugs. Arth. Rheum.22, 877–885 (1979).
B. G. Steinetz, D. C. Swartzendruber, C. Colombo, M. Butler, E. O'Byrne, N. Wuerster and G. Lust,New parameters for evaluation of disease severity in a rabbit model of osteoarthritis. InAdvances in Inflammation Research. Vol. 11. (Ed. I. Otterness et al.) pp. 251–259, Raven Press, New York 1986.
C. P. Sabiston and M. E. Adams,Production of catabolin by synovium from an experimental model of osteoarthritis. J. Orthop. Res.7, 519–529 (1989).
B. G. Steinetz, E. M. O'Byrne, M. C. Butler and L. B. Hickman,Hormonal regulation of the connective tissue of the symphysis pubis. InBiology of Relaxin and its Role in the Human. (Eds. M. Bigazzi, F. C. Greenwood and F. Gasparri) pp. 71–92, Excerpta Medica, Amsterdam, Oxford and Princeton 1983.
L. Wahl, R. Blandau and R. Page,Effect of hormones on collagen metabolism and collagenase activity in the public symphysis ligament of the guinea pig. Endocrinology100, 571–579 (1977).
H. J. Chihal and L. L. Espey,Utilization of the relaxed symphysis pubis of guinea pigs for clues to the mechanism of ovulation. Endocrinology93, 1441–1445 (1973).
B. G. Steinetz, R. L. Kroc and V. L. Beach,Bioassay of relaxin. InMethods in Hormone Research. (Ed. R. I. Dorfman) pp. 481–513 (1969).
E. M. O'Byrne and B. G. Steinetz,Radioimmunoassay (RIA) of relaxin in various species using an antiserum to porcine relaxin. Proc. Soc. Exp. Biol. Med.152, 272–276 (1976).
P. Whiteman,The quantitative measurement of alcian blue-glycosaminoglycan complexes. Biochem. J.131, 343–350 (1973).
F. Kawamura,Effect of glycosaminoglycan-polysulfate on cartilage proteoglycans of experimentally produced osteoarthritis in rabbit knee joints. Nihon Univ. J. Med.23, 129–144 (1981).
J. C. Golding and P. Ghosh,Drugs for osteoarthritis I: The effects of pentosan polysulfate (SP54) on the degradation and loss of proteoglycans from articular cartilage in a model of osteoarthrosis induced in the rabbit knee by immobilization. Current Therap. Res.33, 173–184 (1983).
H. Vanharanta,Glycosaminoglycan polysulfate treatment in experimental osteoarthritis in rabbits. Scand. J. Rheumatol.12, 225–230 (1983).
D. Howell, O. E. Muniz and M. R. Carreno,Effect of glycosaminoglycan polysulfate ester on proteoglycan-degrading enzyme activity in an animal model of osteoarthritis. InAdvances in Inflammation Research. Vol. 11. (Eds. I. Otterness et al.) pp. 197–205, Raven-Press, New York 1986.
G. Lust, A. J. Williams, N. Burton-Wurster, K. A. Beck and G. Rubin,Effect of intramuscular injections of glycosaminoglycan polysulfates on signs of incipient hip dysplasia in growing dogs. Am. J. Vet. Res.53, 1836–1843 (1992).
R. W. Moskowitz, J. H. Reese, R. G. Young, D. Fein-Krantz, C. Malemud and A. I. Caplan,The effects of Rumalon, a glycosaminoglycan peptide complex, in a partial meniscectomy model of osteoarthritis in rabbits. J. Rheumatol.18, 205–209 (1991).
G. S. Gates, J. J. Flynn, R. J. Ryan and O. D. Sherwood,In vivo uptake of 125 I-relaxin in the guinea pig. Biol. Reprod.25, 549–554 (1981).
L. P. Yu, Jr., G. N. Smith, K. D. Brandt, S. L. Myers, B. L. O'Connor and D. A. Brandt,Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. Arth. Rheum.35, 1150–1159 (1992).
M. Lingetti, P. L. D'Ambrosio, F. DiGrezia, P. Sorrentino and E. Lingetti,A controlled study in the treatment of osteoarthritis with diacetylrhein (Artrodar) Curr. Therap. Res.31, 408–412 (1982).
C. Arsenis, R. A. Greenwald, A. Moak and R. S. Laskin,Inhibition of neutral metalloproteinase activities (MTP) in epiphyseal and articular cartilage by tetracyclines (TETS) both in vivo and in vitro. Trans. Orthop. Res. Soc.15, 268 (1990).
M. Mian, D. Benetti, S. Rosini and R. Fantozzi,Rhein reduces proteoglycan loss during the autolytic breakdown of cultured cartilage. Int. J. Tiss. Reac.XI, 117–122 (1989).
J. Martel-Pelletier, J.-P. Pelletier and C. J. Malamud,Activation of neutral metalloprotease in human osteoarthritic knee cartilage: Evidence for degradation in the core protein of sulphated proteoglycan. Ann. Rheum. Dis.47, 801–808 (1988).
D. J. Buttle, C. J. Handley, M. Z. Ilic, J. Saklatvala, M. Murata and A. J. Barrett,Inhibition of cartilage proteoglycan release by a specific inactivator of cathepsin B and an inhibitor of matrix metalloproteinases. Evidence for two converging pathways of chondrocyte-mediated proteoglycan degradation. Arth. Rheum.36, 1709–1717 (1993).
H. Mori, M. Nakagawa, N. Itoh, K., Wada and T. Tamaya,Danazol suppresses the production of interleukin-1β and tumor necrosis factor by human monocytes. Am. J. Reprod. Immunol.24, 45–50 (1990).
B. A. Robertson, L. C. Gahrinh and R. A. Daynes,Neuropeptide regulation of interleukin-1 activities: Capacity of α-melanocyte stimulating hormone to inhibit interleukin-1-inducible responses in vivo and in vitro exhibits target cell selectivity. Inflammation10, 371–385 (1986).
J. M. Lipton, A. Macaluso, M. E. Hiltz and A. Catania,Central andministration of the peptide a-MSH inhibits inflammation in the skin. Peptides12, 795–798 (1991).
T. A. Bird and J. Saklatvala,Identification of a common class of high affinity receptors for both types of porcine interleukin-1 on connective tissue cells. Nature324, 263–266 (1986).
J. Panagides, M. J. Landes and A. E. Sloboda,Destruction of articular cartilage by arthritic synovium in vitro: Mechanism of breakdown and effect of indomethacin and prednisolone. Agents and Actions10, 22–30 (1980).
C. Colombo, M. Butler, L. Hickman, M. Selwyn, J. Chart and B. Steinetz,A new model of osteoarthritis in rabbits: II. Evaluation of antiosteoarthritic effects of selected antirheumatic drugs administered systemically. Arth. Rheum.26, 1132–1139 (1983).
J. Martel-Pelletier, J.-M. Cloutier and J.-P. Pelletier,In vivo effects of antirheumatic drugs on neutral collagenolytic proteases in human rheumatoid arthritis cartilage and synovium. J. Rheumatol.15, 1198–1204 (1988).
A. Weiss, E. Livne and M. Silbermann,Glucocorticoid hormone adversely affects the growth and regeneration of cartilage in vitro. Growth Develop. Aging52, 67–75 (1988).
S. L. Myers, K. D. Brandt and B. L. O'Connor,Low dose prednisone treatment does not reduce the severity of osteoarthritis in dogs after anterior cruciate ligament transection. J. Rheumatol.18, 1856–1862 (1991).
B. G. Steinetz, V. L. Beach and R. L. Kroc,The physiology of relaxin in laboratory animals. InRecent Progress in the Endocrinology of Reproduction. (Ed. C. H. Lloyd) pp. 389–423, Academic Press, New York and London 1959.
J.-P. Pelletier, J.-M. Cloutier and J. Martel-Pelletier,In vitro effects of tiaprofenic acid, sodium salicylate and hydrocortisone on the proteoglycan metabolism of human osteoarthritic cartilage. J. Rheumatol.16, 646–655 (1989).
T. Cawston,Blocking cartilage destruction with metalloproteinase inhibitors: A valid therapeutic target? Ann. Rheum. Dis.52, 769–770 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Steinetz, B.G., Lust, G. Inhibition of relaxin-induced pubic symphyseal “relaxation” in guinea pigs by glycosaminoglycan polysulfates and pentosan polysulfate. Agents and Actions 42, 74–80 (1994). https://doi.org/10.1007/BF02014304
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02014304