Kapila S, Xie Y
Department of Growth and Development, University of California San Francisco 94143-0640, USA.
Lab Invest. 1998 Aug;78(8):925-38.
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.
颞下颌关节（TMJ）相关疾病在女性中的发病率明显高于男性，与其他关节的类似疾病不同，这些疾病主要发生在生育年龄段。尽管女性生殖激素在这些疾病的发病机制中可能起到一定作用，但尚无直接证据表明女性生殖激素与颞下颌关节紊乱之间存在关联，也不清楚这些激素导致颞下颌关节疾病的具体机制。由于松弛素是一种6kd的多肽激素，它能改变耻骨联合纤维软骨的基质组成，并与全身关节活动过度有关，滑膜关节——尤其是那些含有大量纤维软骨组织的关节，如颞下颌关节——是其基质重塑活性的潜在但未经证实的靶点。这些研究的目的是确定松弛素对未用雌激素预处理和经β-雌二醇预处理的颞下颌关节盘纤维软骨细胞中组织降解酶、基质金属蛋白酶（MMPs）及其抑制剂金属蛋白酶组织抑制剂（TIMPs）表达的影响。将早期传代的盘状纤维软骨细胞暴露于浓度逐渐增加的松弛素中，然后检测细胞条件培养基或mRNA中的MMPs和TIMPs。松弛素可剂量依赖性地诱导胶原酶-1（MMP-1）和基质溶解素-1（MMP-3）的表达，但对纤维软骨细胞中TIMP-1和TIMP-2的表达影响极小。用β-雌二醇预处理这些细胞可增强其对松弛素的MMP诱导反应，使得胶原酶-1和基质溶解素-1在雌激素预处理细胞中的最大表达浓度比未预处理细胞低10至100倍。相比之下，单独使用β-雌二醇会导致这些MMPs呈剂量依赖性降低。最后，松弛素对胶原酶-1和基质溶解素-1的诱导作用在纤维软骨细胞中具有特异性，因为在未预处理和雌激素预处理的滑膜细胞中，松弛素都会使这些MMPs呈剂量依赖性降低。这些发现表明，松弛素单独或与β-雌二醇联合作用于纤维软骨盘的降解重塑，提示了松弛素可能使女性易患颞下颌关节疾病的一种机制。
