Mechanical loading of joint modulates T cells in lymph nodes to regulate osteoarthritis.

OBJECTIVE: The crosstalk of joint pathology with local lymph nodes in osteoarthritis (OA) is poorly understood. We characterized the change in T cells in lymph nodes following load-induced OA and established the association of the presence and migration of T cells to the onset and progression of OA. METHODS: We used an in vivo model of OA to induce mechanical load-induced joint damage. After cyclic tibial compression of mice, we analyzed lymph nodes for T cells using flow cytometry and joint pathology using histology and microcomputed tomography. The role of T-cell migration and the presence of T-cell type was examined using T-cell receptor (TCR)α-/- mice and an immunomodulatory drug, Sphingosine-1-phosphate (S1P) receptor inhibitor-treated mice, respectively. RESULTS: We demonstrated a significant increase in T-cell populations in local lymph nodes in response to joint injury in 10, 16, and 26-week-old mice, and as a function of load duration, 1, 2, and 6 weeks. T-cell expression of inflammatory cytokine markers increased in the local lymph nodes and was associated with load-induced OA progression in the mouse knee. Joint loading in TCRα-/- mice reduced both cartilage degeneration (Osteoarthritis Research Society International (OARSI) scores: TCRα 0.568, 0.981-0.329 confidence interval (CI); wild type (WT) 1.328, 2.353-0.749 CI) and osteophyte formation. Inhibition of T-cell egress from lymph nodes attenuated load-induced cartilage degradation (OARSI scores: Fingolimod: 0.509, 1.821-0.142 CI; Saline 1.210, 1.932-0.758 CI) and decreased localization of T cells in the synovium. CONCLUSIONS: These results establish the association of lymph node-resident T cells in joint damage and suggest that the S1P receptor modulators and T-cell immunotherapies could be used to treat OA.

Injectable mechanical pillows for attenuation of load-induced post-traumatic osteoarthritis.

Osteoarthritis (OA) of the knee joint is a degenerative disease initiated by mechanical stress that affects millions of individuals. The disease manifests as joint damage and synovial inflammation. Post-traumatic osteoarthritis (PTOA) is a specific form of OA caused by mechanical trauma to the joint. The progression of PTOA is prevented by immediate post-injury therapeutic intervention. Intra-articular injection of anti-inflammatory therapeutics (e.g. corticosteroids) is a common treatment option for OA before end-stage surgical intervention. However, the efficacy of intra-articular injection is limited due to poor drug retention time in the joint space and the variable efficacy of corticosteroids. Here, we endeavored to characterize a four-arm maleimide-functionalized polyethylene glycol (PEG-4MAL) hydrogel system as a 'mechanical pillow' to cushion the load-bearing joint, withstand repetitive loading and improve the efficacy of intra-articular injections of nanoparticles containing dexamethasone, an anti-inflammatory agent. PEG-4MAL hydrogels maintained their mechanical properties after physiologically relevant cyclic compression and released therapeutic payload in an on-demand manner under in vitro inflammatory conditions. Importantly, the on-demand hydrogels did not release nanoparticles under repetitive mechanical loading as experienced by daily walking. Although dexamethasone had minimal protective effects on OA-like pathology in our studies, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from cartilage degradation and inhibit osteophyte formation in an in vivo load-induced OA mouse model.