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

Receptor activator of NF-kappa B 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.

Automated summary

RANKL is essential for osteoclast formation and bone remodeling, with bone marrow adipose lineage cells being identified as a crucial cellular source for RANKL production. Conditional deletion of RANKL from these cells leads to an increase in cancellous bone mass in mice by reducing trabecular osteoclast formation and bone resorption, providing potential targets for preventing pathological bone loss.