Modulating PTOA development with parathyroid hormone

用甲状旁腺激素调节 PTOA 发育

• 批准号: 10737336
• 负责人: Marjolein C van der Meulen
• 金额: $ 39.61万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737336
• 关键词: Adult; Affect; Anabolism; Attenuated; Biological Process; Bone Resorption; Bone Spur; Bone Tissue; Bone remodeling; Cartilage; Cells; Chondrogenesis; Data; Degenerative polyarthritis; Development; Developmental Process; Disease; Disease Progression; Dose; Event; FDA approved; Female; Gene Expression; Gene Expression Profiling; Genes; Health; Immune response; In Situ Hybridization; Individual; Inflammation; Injury; Joints; Knee; Knee joint; Ligaments; Meniscus structure of joint; Modeling; Morphology; Mus; Neuroimmune; Neuroimmunomodulation; Osteogenesis; Osteoporosis; Outcome; PTH gene; Pain; Paired Comparison; Pathology; Pharmaceutical Preparations; Population; Pre-Clinical Model; Predisposition; Property; Role; Sclerosis; Swelling; Synovial Membrane; Testing; Thick; Tissue-Specific Gene Expression; Tissues; Traumatic Arthropathy; arthropathies; articular cartilage; bone; bone loss; bone mass; cartilage regeneration; clinical practice; cortical bone; disability; experimental study; immune function; immunoregulation; improved; in vivo; joint function; joint injury; joint loading; joint stiffness; loss of function; male; nerve supply; pain reduction; preservation; prevent; response; single-cell RNA sequencing; subchondral bone; transmission process

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.

骨关节炎（OA）是一种关节疾病，是成年人致残的主要原因。关节病理 包括正常软骨形态的破坏，潜在的软骨下骨特性的变化， 并诱导关节边缘骨赘形成。创伤性关节损伤，如半月板和 韧带撕裂或关节软骨损伤增加了发生特定类型OA的易感性， 创伤后关节炎（PTOA）。PTOA与关节损伤的相关性提供了一个明确的事件， 其干预和减弱或抑制随后的OA起始和发展。除了软骨 PTOA损伤，软骨下骨发生进行性变化，开始骨吸收， 这表明靶向骨可以预防早期PTOA。我们开发了一种非侵入性的 用重复负荷诱导OA和用单剂量负荷诱导PTOA的模型 膝盖在我们对该OA模型的初步数据中，间歇性甲状旁腺激素（iPTH）有利于 成年雄性小鼠的关节组织健康，即使iPTH治疗后每天进行6周的损伤 加载中使用PTOA模型，我们发现，当骨 创伤性负荷后立即抑制重塑。 基于这些有趣的结果，我们假设间歇性PTH治疗将抑制 PTOA病理在关节中的发展。我们建议使用我们的负载引起的PTOA来测试这一假设 模型有三个具体目标： (Aim 1）在单次冲击后减弱负荷诱导的组织形态学损伤和细胞反应。 在成年雄性和雌性小鼠中用延迟的iPTH处理破坏体内负荷; (Aim 2）证明疼痛减轻，关节功能维持和神经免疫机制 在单次损伤性体内负荷后立即或延迟2周用iPTH治疗调节， 在成年雄性和雌性小鼠中启动PTOA (Aim 3）确定改变的神经免疫基因表达与减少的组织损伤相关， 来自成年雄性和雌性小鼠的软骨、滑膜和骨，在单次给药后立即用iPTH处理。 一次体内加载以启动PTOA 我们预计iPTH的有益作用将能够克服现有的组织损伤， 通过骨锚定和软骨形成延迟治疗来改变PTOA疾病进展。我们 初步数据表明，使用FDA-专门针对软骨下骨和软骨的作用 批准的骨质疏松症治疗减缓OA进展。iPTH抑制软骨和骨病理 将改变临床实践。