PDF(Pubmed)
Abstract：
Glucocorticoids (GC) and parathyroid hormone (PTH) are widely used therapeutic endocrine hormones where their effects on bone and joint arise from actions on multiple skeletal cell types. In osteocytes, GC and PTH exert opposing effects on perilacunar canalicular remodeling (PLR). Suppressed PLR can impair bone quality and joint homeostasis, including in GC-induced osteonecrosis. However, combined effects of GC and PTH on PLR are unknown. Given the untapped potential to target osteocytes to improve skeletal health, this study sought to test the feasibility of therapeutically mitigating PLR suppression. Focusing on subchondral bone and joint homeostasis, we hypothesize that PTH(1-34), a PLR agonist, could rescue GC-suppressed PLR. The skeletal effects of GC and PTH(1-34), alone or combined, were examined in male and female mice by micro-computed tomography, mechanical testing, histology, and gene expression analysis. For each outcome, females were more responsive to GC and PTH(1-34) than males. GC and PTH(1-34) exerted regional differences, with GC increasing trabecular bone volume but reducing cortical bone thickness, stiffness, and ultimate force. Despite PTH(1-34)\'s anabolic effects on trabecular bone, it did not rescue GC\'s catabolic effects on cortical bone. Likewise, cartilage integrity and subchondral bone apoptosis, tartrate-resistant acid phosphatase (TRAP) activity, and osteocyte lacunocanalicular networks showed no evidence that PTH(1-34) could offset GC-dependent effects. Rather, GC and PTH(1-34) each increased cortical bone gene expression implicated in bone resorption by osteoclasts and osteocytes, including Acp5, Mmp13, Atp6v0d2, Ctsk, differences maintained when GC and PTH(1-34) were combined. Since PTH(1-34) is insufficient to rescue GC\'s effects on young female mouse bone, future studies are needed to determine if osteocyte PLR suppression, due to GC, aging, or other factors, can be offset by a PLR agonist.
摘要：
糖皮质激素（GC）和甲状旁腺激素（PTH）是广泛使用的治疗性内分泌激素，它们对骨骼和关节的作用源于对多种骨骼细胞类型的作用。在骨细胞中，GC和PTH对周泪小管重塑（PLR）产生相反的作用。抑制PLR会损害骨骼质量和关节稳态，包括GC诱导的骨坏死。然而,GC和PTH对PLR的联合作用尚不清楚。鉴于靶向骨细胞改善骨骼健康的潜力尚未开发，本研究旨在验证治疗性缓解PLR抑制的可行性.专注于软骨下骨和关节稳态，我们假设PTH(1-34)，PLR激动剂，可以挽救GC抑制的PLR。GC和PTH（1-34）的骨骼效应，单独或组合，通过微型计算机断层扫描对雄性和雌性小鼠进行了检查，机械测试,组织学,和基因表达分析。对于每个结果，女性对GC和PTH（1-34）的反应高于男性。GC和PTH(1-34)产生了地区差异，GC增加骨小梁体积但减少皮质骨厚度，刚度,最终的力量。尽管PTH(1-34)对小梁骨的合成代谢作用，它不能挽救GC对皮质骨的分解代谢作用。同样，软骨完整性和软骨下骨凋亡，抗酒石酸酸性磷酸酶（TRAP）活性，和骨细胞腔小泡网络显示没有证据表明PTH（1-34）可以抵消GC依赖性作用。相反，GC和PTH（1-34）各自增加皮质骨基因表达，牵涉到破骨细胞和骨细胞的骨吸收，包括Acp5，Mmp13，Atp6v0d2，Ctsk，当GC和PTH（1-34）联合使用时，差异仍然存在。由于PTH（1-34）不足以挽救GC对年轻雌性小鼠骨骼的影响，未来的研究需要确定骨细胞PLR抑制，由于GC，老化，或其他因素，可以被PLR激动剂抵消。
