Abstract
The preponderance of temporomandibular joint (TMJ) degenerative disorders in women and their early onset during reproductive years have implicated female sex hormones, particularly 17-β estradiol (E2), in the pathogenesis of these disorders. Nevertheless, the mechanisms by which E2 contributes to TMJ degenerative disorders and the reasons for its targeted effects on the TMJ but not other joints remain poorly understood. Here, we developed an ovariectomized mouse model in which systemic E2 concentrations mimicked those in cycling women, and we determined the effect of E2 on the targeted turnover of TMJ fibrocartilage matrix via E2-induced matrix metalloproteinases MMP9 and MMP13. Infusion of E2 and progesterone (P4; hormone control) over 7 d resulted in 5- and 8-fold greater serum E2 and P4 levels relative to controls, respectively, achieving systemic hormone levels similar to high baseline levels in cycling women. Administration of E2 but not P4 caused a significant loss of TMJ collagen and glycosaminoglycans, which was accompanied by amplification of ERα and specific increases in MMP9 and MMP13 expression. This dose of E2 had no effect on knee meniscus fibrocartilage, demonstrating the specificity of the degradative effect of E2. Dose-response experiments showed a greater sensitivity and a higher peak induction of MMP9 and MMP13 in TMJ fibrocartilaginous cells than knee meniscus cells to E2, providing an explanation for the differential responses of these tissues to E2. Using MMP9- and MMP13-null mice, we observed no discernible effects of each proteinase individually to E2-mediated TMJ matrix loss but noted a significant compensatory reciprocal induction of each MMP by E2 in the absence of the other. The redundancy in E2's induction of MMP9 and MMP13 suggests that the proteinases may together contribute to E2-mediated TMJ fibrocartilage loss. These results advance our understanding of E2-mediated upregulation of MMP9 and MMP13 on fibrocartilage matrix turnover targeted to the TMJ.