Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis

The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on organ aging. Here, we demonstrate that both transgenic Alzheimer’s disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits. Senescent BMAds acquire a secretory phenotype, markedly increasing secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and promotes insoluble amyloid formation from soluble amyloid-β (Aβ) peptides in in vitro and ex vivo three-dimensional (3D) BMAd-based cultures. Combined SAP/PTX2 and Aβ treatment promotes osteoclastogenesis but inhibits osteoblastogenesis. Transplanting senescent BMAds into the bone marrow cavity of young mice induces bone loss, which is reversed by senolytic treatment. Finally, depleting SAP/PTX2 in aged mice abolishes marrow amyloid deposition and rescues low bone mass. Thus, senescent BMAds drive age-related skeletal amyloidosis and bone deficits via SAP/PTX2. Amyloid fibrils can accumulate in tissues outside the brain, yet the impact is incompletely understood. Here the researchers show that, with age, mouse bone marrow fat cells become senescent and secrete SAP/PTX2, driving amyloid buildup and bone loss. Clearing senescent fat cells or depleting SAP/PTX2 reduces marrow amyloid deposits and restores bone health.