AUTHORS
Ziru Li, Devika P. Bagchi, Junxiong Zhu, Emily Bowers, Hui Yu, Julie Hardij, Hiroyuki Mori, Katrina Granger, Jon Skjaerlund, Gurjit Mandair, Simin Abrishami, Kanakadurga Singer, Kurt D. Hankenson, Clifford J. Rosen, and Ormond A. MacDougald
ABSTRACT
Bone marrow adipocytes (BMAd) are a unique cell population derived from bone marrow mesenchymal progenitors and marrow adipogenic lineage precursors. Although they have long been considered to be a space-filler within bone cavities, recent studies have revealed important physiological roles in hematopoiesis and bone metabolism. To date, the approaches used to study BMAd function have been confounded by contributions by non-marrow adipocytes or by bone marrow stromal cells. To address this gap in the field, we have developed a BMAdspecific Cre mouse model to deplete BMAds by expression of diphtheria toxin A (DTA), or by deletion of peroxisome proliferator-activated receptor gamma (Pparg). We found that DTAinduced loss of BMAds results in decreased hematopoietic stem and progenitor cell numbers and increased bone mass in BMAd-enriched locations, including the distal tibiae and caudal vertebrae. Elevated bone mass appears to be secondary to enhanced endosteal bone formation, suggesting a local effect caused by depletion of BMAd. Augmented bone formation with BMAd-depletion protects mice from bone loss induced by caloric restriction or ovariectomy,
and facilitates the bone healing process after fracture. Finally, ablation of Pparg also reduces BMAd numbers and largely recapitulates high bone mass phenotypes observed with DTAinduced BMAd depletion.