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,但它的功能大多是未知的。我们假设PR可能调节软骨细胞代谢并影响软骨下骨结构。
我们利用遗传命运作图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作用,我们选择性地删除了由Prx1(Prx1;PRcKO)和胶原蛋白2(Col2;PRcKO)标记的骨软骨祖细胞中的PR,或以聚集蛋白聚糖(Acan;PRcKO)标记的成熟软骨细胞,并在4个月大时评估软骨下骨结构。通过抗衰老标记p16INK4a监测软骨细胞衰老,和MMP13,衰老相关秘书表型(SASP)组件之一。
与野生型(WT)小鼠相比,雌性Prx1;PRcKO和Col2;PRcKO小鼠有更大的软骨下骨总体积和更大的软骨下皮质骨厚度,雌性和雄性Col2;PRcKO小鼠的估计软骨下骨刚度和衰竭负荷均增加。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,我们在Acan;PRcKO小鼠中没有观察到任何软骨下骨变化,除了在雄性Acan;PRcKO小鼠中观察到更高的工作至失败。尽管在WT和PR之间的关节软骨中没有检测到差异;软骨细胞条件性缺失小鼠,有更多数量的衰老软骨细胞和增加的MMP13表达,尤其是雄性突变小鼠。
这些研究结果表明,选择性抑制骨祖细胞中的PR,但不是在终末分化的软骨细胞中,诱导增加的软骨下骨表型和高估计的软骨下骨强度,这可能与老年骨关节炎的发展有关。
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.
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.
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.
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.