Grancalcin in Immune Cells is Induced and Regulates Bone-Fat Imbalance During Skeletal Aging

Skeletal aging is characterized by low bone turnover and increased marrow fat accumulation. However, the underlying mechanism remains poorly defined. Here we show that pro-inflammatory and senescent subtypes of immune cells, including macrophages and neutrophils, accumulated in bone marrow and secreted abundant grancalcin (GCA) during aging. Elevation of bone marrow GCA level in young mice leads to premature skeletal aging. Deletion of GCA in neutrophils and macrophages rejuvenates skeletal aging. Mechanistically, we identify that GCA binds to Plexin-b2 receptor and inactivates its downstream pathway. Depletion of plexin-b2 in bone marrow mesenchymal stem cells abrogates the rejuvenated bone phenotype of GCA-knockout mice. Moreover, GCA neutralizing antibody is generated and shows a certain rejuvenating effect on bone. Given that immune cells are involved into diverse pathologic processes, targeting this fundamental mechanism to prevent skeletal aging offers novel treatment strategy not only for osteoporosis, but also for multiple age-related diseases.