Senescent immune cells promote skeletal ageing

Abstract

0123456789();: Nature reviews | Endocrinology New research published in Cell Metabolism sheds light on a novel mechanism of skeletal ageing, in which senescent immune cells accumulate in the bone marrow and secrete grancalcin (a calcium-binding protein). In bone marrow under homeostatic conditions, a balance exists between osteogenesis and adipogenesis. During ageing, this balance is disrupted, leading to accumulation of adipose in bone marrow and low bone turnover, which can cause age-related osteoporosis. “Data from the mass spectrometry analysis of bone marrow supernatant from young and older rats revealed an immune cell-secreted protein, grancalcin,” explains corresponding author Xianghang Luo. “After testing the effects of grancalcin on osteogenesis and adipogenesis, we decided to investigate the role of grancalcin on skeletal ageing.” In vitro investigations showed that grancalcin represses osteogenesis and osteoclastogenesis while promoting adipogenesis. To test these effects in vivo, the researchers injected young mice with human recombinant grancalcin or control once per week for 4 weeks. Notably, the grancalcin-treated young mice showed decreased bone turnover and increased accumulation of adipose in bone marrow, the hallmarks of ageing. Next, single-cell RNA-sequencing analysis was used to show that grancalcin-positive proinflammatory and senescent neutrophils and macrophages accumulated within the bone marrow of old rats. A mouse model with knockout of the gene encoding grancalcin (Gca) specifically in neutrophils and macrophages (Gca-KO mice) was generated. Importantly, Gca-KO mice showed delayed age-related bone loss. Furthermore, Gca-KO mice had a greater number and surface area of osteoblasts and a lower number and surface area of bone marrow adipocytes than wild-type mice. Mass spectrometry and in vitro assays identified plexin B2 as the functional receptor of grancalcin in bone marrow mesenchymal stromal cells (BMSCs). Grancalcin binds to plexin B2 on BMSCs and inactivates downstream signalling by supressing phosphorylation of FAK–SRC–YAP. The researchers generated a mouse model with heterozygous deletion of Plxnb2 in BMSCs, which had decreased bone mass. Furthermore, heterozygous Plxnb2 deletion in BMSCs of Gca-KO mice prevented their improved bone phenotype. Finally, the researchers generated a monoclonal antibody that neutralized grancalcin activity. Old mice received an intravenous tail injection of this antibody twice per week for 2 months; these mice showed improved skeletal health compared with control mice. “In the future, we plan to continue to investigate the function of grancalcin+ immune cells in the degeneration and regeneration of multiple tissues,” concludes Luo. In addition, this research indicates that grancalcin might be a promising drug target for the treatment of age-related osteoporosis. Shimona Starling B O N E