Journal
JCI INSIGHT
Volume 7, Issue 21, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.160915
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Funding
- NIH [R24 DK092759, DK125513, DK121759, DK130879, R01 AG069795, T32 HD007505, T32 GM007863, R01DK115583, R01AR066028, R24DK092759]
- American Diabetes Association [1-18-PDF-087]
- American Heart Association [20-PAF00361]
- Pilot & Feasibility grant
- Michigan Integrative Musculoskeletal Health Core Center [P30 AR069620]
- Michigan Diabetes Research Center (P30 DK020572), Michigan Nutrition and Obesity Center [P30 DK089503]
- University of Michigan Comprehensive Cancer Center [P30 CA046592]
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BM adipocytes play important roles in hematopoiesis and bone metabolism, and their depletion leads to increased bone mass and decreased hematopoietic stem cell numbers. Depletion of BM adipocytes protects mice from bone loss and facilitates bone healing.
BM adipocytes (BMAd) are a unique cell population derived from BM 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 nonmarrow adipocytes or by BM stromal cells. To address this gap in the field, we have developed a BMAd-specific 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 DTA-induced 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 it facilitates the bone-healing process after fracture. Finally, ablation of Pparg also reduces BMAd numbers and largely recapitulates high-bone mass phenotypes observed with DTA-induced BMAd depletion.
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