RANKL from bone marrow adipose lineage cells promotes osteoclast formation and bone loss

Receptor activator of NF-κB ligand (RANKL) is essential for osteoclast formation and bone remodeling. Nevertheless, the cellular source of RANKL for osteoclastogenesis has not been fully uncovered. Different from peripheral adipose tissue, bone marrow (BM) adipose lineage cells originate from bone marrow mesenchymal stromal cells (BMSCs). Here, we demonstrate that adiponectin promoter-driven Cre expression ( Adipoq Cre ) can target bone marrow adipose lineage cells. We cross the Adipoq Cre mice with rankl fl/fl mice to conditionally delete RANKL from BM adipose lineage cells. Conditional deletion of RANKL increases cancellous bone mass of long bones in mice by reducing the formation of trabecular osteoclasts and inhibiting bone resorption but does not affect cortical bone thickness or resorption of calcified cartilage. Adipoq Cre ; rankl fl/fl mice exhibit resistance to estrogen deficiency and rosiglitazone (ROS)-induced trabecular bone loss but show bone loss induced by unloading. BM adipose lineage cells therefore represent an essential source of RANKL for the formation of trabecula osteoclasts and resorption of cancellous bone during remodeling under physiological and pathological conditions. Targeting bone marrow adiposity is a promising way of preventing pathological bone loss. Synopsis RANKL is essential for osteoclast formation and bone remodeling, but the cellular source for osteoclastogenesis has not been fully uncovered. Bone marrow adipose lineage cells are essential RANKL sources for trabecular osteoclast formation and bone resorption in the context of pathological bone loss. The Adipoq Cre line targets bone marrow adipose lineage cells. Conditional knockout of RANKL in bone marrow adipose lineage cells increases cancellous bone mass by reducing formation of trabecular osteoclasts and inhibiting bone resorption. Adipoq Cre ; rankl fl/fl mice exhibit resistance to estrogen deficiency and rosiglitazone induced trabecular bone loss but show bone loss induced by unloading. Graphical Abstract Bone marrow adipose lineage cells are an essential source of RANKL for trabecular osteoclast formation and bone resorption in the context of pathological bone loss.