Temporomandibular joint (TMJ)-related diseases have a high female-to-male predilection and, unlike similar diseases of other joints, occur primarily during reproductive years. Although a role of female reproductive hormones has been proposed in the etiopathogenesis of these diseases, no direct evidence exists to link female reproductive hormones to TMJ disorders or to define the mechanisms by which these hormones may predispose to TMJ disease. Because relaxin, a 6-kd polypeptide hormone, alters the matrix composition of pubic symphyseal fibrocartilage and has been implicated in systemic joint hypermobility, synovial joints--particularly those with a large component of fibrocartilaginous tissues such as the TMJ--are potential but unproved target sites for its matrix-remodeling activity. The purpose of these studies was to determine the effects of relaxin on the expression of tissue-degrading enzymes, matrix metalloproteinases (MMPs), and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), in unprimed and beta-estradiol-primed TMJ disc fibrocartilaginous cells. Early-passage disc fibrocartilaginous cells were exposed to increasing concentrations of relaxin, and the cell-conditioned medium or mRNA was assayed for MMPs and TIMPs. Relaxin produced a dose-dependent induction of collagenase-1 (MMP-1) and stromelysin-1 (MMP-3), but minimal modulation of TIMP-1 and TIMP-2 expression in the fibrocartilaginous cells. Priming of these cells with beta-estradiol potentiated their MMP-inductive response to relaxin such that the maximal expression of collagenase-1 and stromelysin-1 occurred at 10- to 100-fold lower concentrations of relaxin in estrogen-primed than in unprimed cells. By contrast, beta-estradiol alone caused a dose-dependent decrease in these MMPs. Finally, relaxin's induction of collagenase-1 and stromelysin-1 was specific to the fibrocartilaginous cells, because in both unprimed and estrogen-primed synoviocytes, relaxin produced a dose-dependent decrease in these MMPs. These findings implicate relaxin alone, or in combination with beta-estradiol, in the degradative remodeling of the fibrocartilaginous disc and suggest a mechanism by which relaxin may predispose women to TMJ disease.