A2M and osteoporosis: Herein, we identify A2m as a highly downregulated transcript in BM resident Lin−LEPR+ SSPCs from elderly vs. mature mice and show that silencing its expression in human BM-MSCs recapitulates key aspects of age-induced SSPC dysfunction in vivo. These findings, together with phenotypic data from HOM A2m mice, identify A2M as a putative disease modifying protein in senile osteoporosis.