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Modulating PTOA development with parathyroid hormone

用甲状旁腺激素调节 PTOA 发育

基本信息

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
项目类别：
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

项目摘要

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，是成人致残的主要原因。联合病理