OBJECTIVE The presence or relative proportion of progesterone nuclear receptors (PR) in different tissues may contribute to sexual dimorphism in these tissues. PR is expressed in chondrocytes, but its function is mostly unknown. We hypothesized that the PR may regulate chondrocyte metabolism and affect subchondral bone structure. METHODS We utilized genetic fate mapping and immunohistochemistry to elucidate PR expression in and effect on cartilage. To define sex-dependent and chondrocyte-specific effects of the PR on subchondral bone, we selectively deleted PR in osteochondrogenic progenitor cells marked by Prx1 (Prx1; PRcKO) and Collagen 2 (Col2; PRcKO), or in matured chondrocytes marked by aggrecan (Acan; PRcKO) and evaluated subchondral bone structure at 4 months of age. Chondrocyte aging was monitored by anti-senescence marker, p16INK4a, and MMP13, one of the Senescence-Associated Secretary Phenotype (SASP) components. RESULTS Compared to wild-type (WT) mice, the female Prx1; PRcKO and the Col2; PRcKO mice had greater total subchondral bone volume and greater subchondral cortical bone thickness, with increased estimated subchondral bone stiffness and failure load in both female and male Col2; PRcKO mice. Moreover, Col2; PRcKO mice from both sexes had greater bone formation and bone strength at the femurs. In contrast, we did not observe any subchondral bone changes in Acan; PRcKO mice other than higher work-to-failure observed in the male Acan; PRcKO mice. Despite no detected difference in articular cartilage between the WT and the PR; chondrocyte conditional deletion mice, there were greater numbers of senescent chondrocytes and increased MMP13 expression, especially in the male mutant mice. CONCLUSION These findings suggest that selective inhibition of PR in osteoprogenitor cells, but not in terminally differentiated chondrocytes, induced an increased subchondral bone phenotype and high estimated subchondral bone strength, which might be associated with the development of osteoarthritis in older age.

中文翻译：

---

选择性抑制骨软骨祖细胞中的孕酮受体，而不是成熟软骨细胞，调节软骨下骨结构

目的 不同组织中孕酮核受体 (PR) 的存在或相对比例可能导致这些组织中的性二态性。PR 在软骨细胞中表达，但其功能大多未知。我们假设 PR 可能调节软骨细胞代谢并影响软骨下骨结构。方法 我们利用遗传命运图谱和免疫组织化学来阐明 PR 在软骨中的表达和对软骨的影响。为了定义 PR 对软骨下骨的性别依赖性和软骨细胞特异性影响，我们选择性地删除了以 Prx1 (Prx1; PRcKO) 和胶原蛋白 2 (Col2; PRcKO) 标记的骨软骨形成祖细胞中的 PR，或以蛋白聚糖标记的成熟软骨细胞中的 PR。 Acan；PRcKO) 并在 4 个月大时评估了软骨下骨结构。通过抗衰老标志物 p16INK4a 监测软骨细胞老化，和 MMP13，衰老相关的秘书表型 (SASP) 组件之一。结果 与野生型 (WT) 小鼠相比，雌性 Prx1；PRcKO 和 Col2；PRcKO 小鼠具有更大的总软骨下骨体积和更大的软骨下皮质骨厚度，雌性和雄性 Col2 的估计软骨下骨刚度和失败负荷增加；PRcKO 小鼠。此外，Col2；来自两性的 PRcKO 小鼠在股骨处具有更大的骨形成和骨强度。相比之下，我们没有观察到 Acan 的任何软骨下骨变化。除了在雄性 Acan 中观察到的更高的工作失败率以外的 PRcKO 小鼠；PRcKO 小鼠。尽管在 WT 和 PR 之间没有检测到关节软骨的差异；软骨细胞条件性缺失小鼠，衰老的软骨细胞数量更多，MMP13表达增加，特别是在雄性突变小鼠中。结论 这些研究结果表明，选择性抑制骨祖细胞中的 PR，而不是终末分化的软骨细胞，诱导软骨下骨表型增加和估计的软骨下骨强度增加，这可能与老年骨关节炎的发展有关。