Effects of estradiol on reduction of osteoarthritis in rabbits through effect on matrix metalloproteinase proteins

Document Type : Original Article


1 Research on 2013 Stage Doctoral Student of Shandong University of Traditional Chinese Medicine

2 Department of Orthopaedic Surgery, General Hospital of Jinan Military Command, Jinan, China, 250031

3 Department of Orthopedics, Affiliated Hospital of Taishan Medical University, Taian, China, 271000

4 Shandong University of Traditional Chinese Medicine, Jinan, China, 250014

5 Department of Hepatobiliary Surgery, General Hospital of Jinan Military Command, Jinan, China, 250031


Objective(s): Osteoarthritis (OA), as a known degenerative joint disease, is the most common form of arthritis. In this study, we aimed to elucidate unclear pathogenesis of OA.
Materials and Methods: Rabbit models of OA were established by the transection of the anterior cruciate ligament. Rabbits were randomly divided into three equal groups: the experimental group (OA modeling, treated with estradiol), the control group (OA modeling, treated with normal saline) and the normal group (without OA modeling). The glycosaminoglycan (GAG) and hyaluronan (HA) content of knee joint were collected and assayed. In addition, gene expression of matrix metalloproteinase (MMP)-1, MMP-13 and tissue inhibitor of metalloproteinase (TIMP)-1 were evaluated by real-time PCR and Western blot analysis.
Results: Animal models were developed successfully. GAG and HA concentrations were significantly increased in the experimental and the normal group compared with the control group (PP<0.01, respectively). Significant increase of GAG level in 6, 9 and 12 week-samples were found in the experimental group compared with the control group (P<0.01). The expression level of MMP-1 and MMP-13 in the experimental group were lower than the control group (P<0.01), but still higher than those of the normal group (P<0.01). TIMP-1 expression level was found to be higher in the experimental group than that of the control and normal group (P<0.01).
Conclusion: The results suggested the possible role of estradiol in the pathological process of OA via its effect on the MMPs. The results also implied the effect of estradiol intervention on OA.


1. Attur M, Samuels J, Krasnokutsky S, Abramson SB. Targeting the synovial tissue for treating osteoarthritis (OA): where is the evidence? Best Pract Res Clin Rheumatol 2010; 24:71-79.
2.   Spector T, Nandra D, Hart D, Doyle D. Is hormone replacement therapy protective for hand and knee osteoarthritis in women?: The Chingford Study. Ann Rheum Dis 1997; 56:432-434.
3.   Goldring MB, Berenbaum F. The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide. Clic Orthop Relat R 2004;427:S37-46.
4.   Kitazawa R, Kimble R, Vannice J, Kung V, Pacifici R. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest 1994; 94:2397-2406.
5.   Tanko L, Søndergaard B-C, Oestergaard S, Karsdal M, Christiansen C. An update review of cellular mechanisms conferring the indirect and direct effects of estrogen on articular cartilage. Climacteric 2008; 11:4-16.
6.   Felson DT, Kim YJ. The futility of current approaches to chondroprotection. Arthritis Rheum 2007; 56:1378-1383.
7.   Hayami T, Pickarski M, Wesolowski GA, Mclane J, Bone A, Destefano J, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum 2004; 50:1193-1206.
8.   Felson DT. Epidemiology of hip and knee osteoarthritis. Epidemiol Rev 1988; 10:1-28.
9.   Claassen H, Steffen R, Hassenpflug J, Varoga D, Wruck CJ, Brandenburg LO, et al. 17β-estradiol reduces expression of MMP-1,-3, and-13 in human primary articular chondrocytes from female patients cultured in a three dimensional alginate system. Cell Tissue Res 2010; 342:283-293.
10. Lee YJ, Lee EB, Kwon YE, Lee JJ, Cho WS, Kim HA, et al. Effect of estrogen on the expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 and tissue inhibitor of metalloproternase-1 in osteoarthritis chondrocytes. Rheumatol Int 2003; 23:282-288.
11. Li X, Lang W, Ye H, Yu F, Li H, Chen J, et al. Tougu Xiaotong capsule inhibits the tidemark replication and cartilage degradation of papain-induced osteoarthritis by the regulation of chondrocyte autophagy. Int J Mol Med 2013; 31:1349-1356.
12. Adatia A, Rainsford K, Kean WF. Osteoarthritis of the knee and hip. Part I: aetiology and pathogenesis as a basis for pharmacotherapy. J Pharm Pharmacol 2012; 64:617-625.
13. Hurst R. Structure, function, and pathology of proteoglycans and glycosaminoglycans in the urinary tract. World J Urol 1994; 12:3-10.
14. Chan F, Choi H, Underhill C. Hyaluronan and chondroitin sulfate proteoglycans are colocalized to the ciliary zonule of the rat eye: a histochemical and immunocytochemical study. Histochem Cell Biol 1997; 107:289-301.
15. Yang J, Lü J, Shen X. Effects of estrogen on the changes of proteoglycan in articular cartilage matrix of rabbits with osteoarthritis [J]. J Xi'an Jiaotong Univ 2004; 25:584-586.
16. Song Y, Wu Z, Lin S, Weng X, Qiu G. The effect                of estrogen and progestin on the expression of  matrix metalloproteinases, tissue inhibitor of metalloproteinase and interleukin-1beta mRNA in synovia of OA rabbit model. Natl Med J China 2003; 83:498-503.
17. Ashford S, Williard J. Osteoarthritis: A review.
Nurse Pract 2014; 39:1-8.
18. Grenier S, Bhargava MM, Torzilli PA. An in vitro model for the pathological degradation of articular cartilage in osteoarthritis. J Biomech 2014; 47:645-652.
19. Heinegård D, Saxne T. The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol 2011; 7:50-56.
20. Giacalone PL, Daurés JP, Faure JM, Boulot P, Hedon B, Laffargue F. The effects of mifepristone on uterine sensitivity to oxytocin and on fetal heart rate patterns. Eur J Obstet Gynecol Reprod Biol 2001; 97:30-34.
21. Wu H, Du J, Hu Y, Liu W, Fu G, Zhang J. Expression of MMP-1 MMP-13 and TlMP-1 mRNA in cartilage and synovium of experimentally induced rabbit ACLT osteoarthritis [J]. Chin J Rheumatol 2002; 6:169-173.
22. Taskiran D, Stefanovicracic M, Georgescu H, Evans C. Nitric-oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem Biophys Res Commun 1994; 200:142-148.
23. Pottenger LA, Webb JE, Lyon NB. Kinetics of extraction of proteoglycans from human cartilage. Arthritis Rheum 1985; 28:323-330.
24. Loeser RF. Chondrocyte integrin expression and function. Biorheology 2000; 37:109-116.
25. Rhee JS, Diaz R, Korets L, Hodgson JG, Coussens LM. TIMP-1 alters susceptibility to carcinogenesis. Cancer Res 2004; 64:952-961.
26. Sniekers Y, Weinans H, Bierma-Zeinstra S, Van Leeuwen J, Van Osch G. Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment–a systematic approach. Osteoarthritis Cartilage 2008; 16:533-541.
27. Imgenberg J, Rolauffs B, Grodzinsky A, Schünke M, Kurz B. Estrogen reduces mechanical injury-related cell death and proteoglycan degradation in mature articular cartilage independent of the presence of the superficial zone tissue. Osteoarthritis Cartilage 2013; 21:1738-1745.
28. Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 1990; 343:336-340.
29. Parker DA, Beatty KT, Giuffre B, Scholes CJ, Coolican MR. Articular cartilage changes in patients with osteoarthritis after osteotomy. Am J Sport Med 2011; 39:1039-1045.