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，也是成年人残疾的主要原因。关节病理学 包括正常软骨形态的破坏、底层软骨下骨特性的变化、 以及诱导关节边缘骨赘形成。外伤性关节损伤，例如半月板和 韧带撕裂或关节软骨损伤会增加患特定类型 OA 的可能性， 创伤后关节炎（PTOA）。 PTOA 与关节损伤的关联在术后提供了明确的事件 干预并减弱或抑制随后的 OA 发生和发展。除了软骨之外 PTOA 损伤，软骨下骨逐渐发生变化，并以骨吸收开始 损失，表明靶向骨可以预防早期 PTOA。我们开发了一种非侵入式 通过重复负载诱导 OA 的模型以及通过对小鼠施加单剂量负载诱导 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 周的损害 加载中。使用 PTOA 模型，我们发现当骨 创伤负荷后重塑立即受到抑制。 基于这些有趣的结果，我们假设间歇性 PTH 治疗会抑制 关节中 PTOA 病理学的发展。我们建议使用我们的负载诱导 PTOA 来测试这个假设 模型的三个具体目标： （目标 1）减轻单次负荷后引起的组织形态损伤和细胞反应 延迟 iPTH 治疗会损害成年雄性和雌性小鼠的体内负荷； （目标 2）证明减轻疼痛、维持关节功能和神经免疫机制 在单次破坏性体内负荷后立即用 iPTH 治疗进行调节或延迟 2 周 在成年雄性和雌性小鼠中启动 PTOA （目标 3）确定神经免疫基因表达的改变与组织损伤的减少相关 成年雄性和雌性小鼠的软骨、滑膜和骨骼在单次注射后立即接受 iPTH 治疗 启动 PTOA 的体内加载回合 我们期望 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形成延迟治疗来改变 PTOA 疾病进展。我们的 初步数据表明使用 FDA-专门针对软骨下骨和软骨的作用 批准减缓 OA 进展的骨质疏松症治疗方法。 iPTH 对软骨和骨病理的抑制 关节创伤后的治疗将改变临床实践。