Modulating PTOA Development with Parathyroid Hormone

Co-PI: Heidi Reesink

Department of Clinical Sciences
Sponsor: NIH-National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Grant Number: 1R01AR081943-01A1
Title: Modulating PTOA Development with Parathyroid Hormone
Project Amount: $7,972
Project Period: September 2023 to August 2024

DESCRIPTION (provided by applicant): 

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.