Modulating PTOA development with parathyroid hormone

骨性关节炎(OA)是一种关节疾病，也是成人致残的主要原因。关节病理学 包括正常软骨形态的破坏，潜在软骨下骨特性的变化， 以及在关节边缘诱导骨赘形成。创伤性关节损伤，如半月板和 韧带撕裂或关节软骨损伤会增加发生特定类型骨性关节炎的易感性， 创伤后关节炎(PTOA)。PTOA与关节损伤的关联提供了一个明确的事件 从而干预、减弱或抑制随后的骨性关节炎的启动和发展。除了软骨 PTOA的损害，软骨下骨的进行性改变，开始于骨吸收和 丢失，提示靶向骨骼可以预防早期PTOA。我们已经开发出一种非侵入性的 重复负荷致小鼠骨性关节炎和单次负荷致小鼠PTOA模型 膝盖。在我们这个骨性关节炎模型的初步数据中，间歇性甲状旁腺激素(IPTH)对 成年雄性小鼠的关节组织健康，即使在iPTH治疗之后每天6周的损害 正在装车。使用PTOA模型，我们发现当骨量增加时，负荷引起的关节损伤减弱 创伤负荷后即刻重塑受到抑制。 基于这些有趣的结果，我们假设间歇性甲状旁腺素治疗将抑制 PTOA在关节内的病理学进展。我们建议使用我们的负荷诱导的PTOA来检验这一假设 三个具体目标的模式： (目标1)减轻单次运动后负荷诱导的组织形态损伤和细胞反应 延迟iPTH治疗对成年雄性和雌性小鼠体内负荷的损害； (目标2)证明疼痛减轻、关节功能维持和神经免疫机制 在单次体内破坏性负荷后立即或延迟2周使用iPTH治疗 成年雄性和雌性小鼠启动PTOA (目的3)确定神经免疫基因表达改变与减少组织损伤有关 成年雄性和雌性小鼠的软骨、滑膜和骨在单次注射后立即用iPTH处理 一轮体内负荷以启动PTOA 我们预计iPTH的有益作用将能够克服现有的组织损伤和 通过骨合成代谢和软骨生成，通过延迟治疗来改变PTOA的疾病进展。我们的 初步数据显示，FDA对软骨下骨和软骨具有特定的靶向作用。 批准的骨质疏松症治疗方法可以延缓骨性关节炎的进展。IPTH对软骨和骨病理的抑制作用 关节创伤后将改变临床实践。

Osteoarthritis (OA) is a joint disease and the major cause of disability in the adult population. Joint pathology includes disruption of normal cartilage morphology, changes in the underlying subchondral bone properties, and induction of osteophyte formation at the joint margins. Traumatic joint injuries such as meniscus and ligament tears or articular cartilage damage increase the susceptibility of developing a specific type of OA, post-traumatic arthritis (PTOA). The association of PTOA with a joint injury provides a well-defined event after which to intervene and attenuate or inhibit subsequent OA initiation and development. In addition to cartilage damage with PTOA, progressive changes to subchondral bone develop that initiate with bone resorption and loss, suggesting that targeting bone could prevent early-stage PTOA. We have developed a non-invasive model that induces OA with repetitive loading and PTOA with a single dose of loading applied to the mouse knee. In our preliminary data with this OA model, intermittent parathyroid hormone (iPTH) was beneficial to joint tissue health in adult male mice, even when iPTH treatment was followed by 6 weeks of damaging daily loading. Using the PTOA model, we found that load-induced joint damage was attenuated when bone remodeling was inhibited immediately after traumatic loading. Based on these intriguing results, we hypothesize that intermittent PTH treatment will inhibit the development of PTOA pathology in the joint. We propose to test this hypothesis using our load-induced PTOA model in three specific aims: (Aim 1) To attenuate load-induced tissue morphological damage and cellular responses after a single bout of damaging in vivo loading with delayed iPTH treatment in adult male and female mice; (Aim 2) To demonstrate that pain is reduced, joint function maintained and neuroimmune mechanisms modulated with iPTH treatment immediately or delayed 2 wks after a single bout of damaging in vivo loading to initiate PTOA in adult male and female mice (Aim 3) To identify altered neuroimmune gene expression is correlated with reduced tissue damage in cartilage, synovium and bone from adult male and female mice treated with iPTH immediately after a single bout of in vivo loading to initiate PTOA We expect that the beneficial effects of iPTH will be able to overcome existing tissue damage and modify PTOA disease progression with delayed treatment through bone anabolism and chondrogenesis. Our preliminary data demonstrate a role for specifically targeting the subchondral bone and cartilage using FDA- approved osteoporosis treatments in slowing OA progression. iPTH inhibition of cartilage and bone pathology following joint trauma will transform clinical practice.