Senescent Immune Cells Drive Age-Related Osteoarthritis via Gca-Plxinb2 Axis

Osteoarthritis (OA) is a common degenerative disease and lacks effective treatment because of the limited knowledge regarding the underlying pathophysiology. Aging stands as the foremost risk factor for OA. During aging, aged immune system drives systemic senescence and ageing of solid organs. However, whether and how aged immune cells regulate OA is unclear. This study aims to examine the role of senescent immune cells in OA. To explore the contribution of aged immune cells to OA, young (3 months old) recipient mice were irradiated before injection of donor bone marrow cells from either young (3 months old) or aged (24 months old) mice. Histological analysis was performed to determine the cartilage degeneration. Then we performed single-cell RNA-sequencing to analyze immune cells population in synovium of receipt mouse. The role of senescent macrophages in OA was measured in young mice with intra-articular injection of young or aged macrophages. Macrophages conditional Gca gene knockout mice and chondrocytes conditional Plexinb2 gene knockout mice were constructed to clarify the role of GCA-PlexinB2 axis in age-related OA. Cartilage degeneration in aged mice intra-articularly injected with GCA neutralizing antibody was analyzed. Transplantation of aged bone marrow immune cells leads to degeneration of knee joint of young receipt mice. Single-cell sequencing analysis of synovium in receipt mouse revealed that senescent macrophages migrate to synovium and secret senescence-associated secretory phenotype (SASP) factors, including grancalcin (GCA). Knock out of Gca gene in macrophage delayed the joint degeneration in aged mice. Mechanistic study reveals that GCA leads to metabolic imbalance of chondrocytes through inactivating Plexin-B2 receptors. More importantly, local administration of GCA-neutralizing antibody mitigates OA in aged mice. During aging, senescent macrophages migrate to synovium, inducing chondrocytes dysfunction and driving OA via GCA- Plexin-B2 axis. These findings illustrate that senescent immune cells play vital roles in joint degeneration and provide therapeutic targets for treating OA.