Ablation of Fat Cells in Adult Mice Induces Massive Bone Gain
Wei Zou1, Nidhi Rohatgi2, Jonathan R Brestoff3
1Division of Anatomic and Molecular Pathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Adipocytes control bone mass, but the mechanism is unclear. To explore the effect of postnatal adipocyte elimination on bone cells, we mated mice expressing an inducible primate diphtheria toxin receptor (DTR) to those bearing adiponectin (ADQ)-Cre. DTR activation eliminates peripheral and marrow adipocytes in these DTRADQ mice. Within 4 days of DTR activation, the systemic bone mass of DTRADQ mice began to increase due to stimulated osteogenesis, with a 1,000% expansion by 10-14 days post-DTR treatment. This adipocyte ablation-mediated enhancement of skeletal mass reflected bone morphogenetic protein (BMP) receptor activation following the elimination of its inhibitors, associated with simultaneous epidermal growth factor (EGF) receptor signaling. DTRADQ-induced osteosclerosis is not due to ablation of peripheral adipocytes but likely reflects the elimination of marrow ADQ-expressing cells. Thus, anabolic drugs targeting BMP receptor inhibitors with short-term EGF receptor activation may be a means of profoundly increasing skeletal mass to prevent or reverse pathological bone loss.
Insights
Eliminating adipocytes in mice stimulated bone growth, significantly increasing bone mass. This suggests targeting bone morphogenetic protein (BMP) and epidermal growth factor (EGF) receptors may treat bone loss.
Area of Science:
- Bone Biology and Metabolism
- Adipocyte Biology
- Skeletal Physiology
Background:
- Adipocytes play a crucial role in regulating bone mass, but the underlying mechanisms remain incompletely understood.
- Investigating the impact of adipocyte depletion on skeletal homeostasis is essential for understanding bone regulation.
Purpose of the Study:
- To elucidate the effects of postnatal adipocyte elimination on bone cell activity and overall bone mass.
- To explore the molecular pathways, including bone morphogenetic protein (BMP) and epidermal growth factor (EGF) signaling, involved in adipocyte ablation-induced bone changes.
Main Methods:
- Utilized a genetic model (DTRADQ mice) by mating mice expressing an inducible diphtheria toxin receptor (DTR) with adiponectin (ADQ)-Cre mice.
- Administered diphtheria toxin (DTR activation) to selectively eliminate peripheral and marrow adipocytes.
- Quantified systemic bone mass changes and analyzed molecular signaling pathways (BMP and EGF receptors) post-treatment.
Main Results:
- Adipocyte elimination in DTRADQ mice led to a rapid and significant increase in systemic bone mass, with up to a 1,000% expansion within 10-14 days.
- This osteosclerosis was attributed to stimulated osteogenesis, driven by bone morphogenetic protein (BMP) receptor activation due to the removal of its inhibitors.
- Simultaneous epidermal growth factor (EGF) receptor signaling was observed, and the effect was linked to the elimination of marrow adiponectin-expressing cells, not peripheral adipocytes.
Conclusions:
- Postnatal elimination of marrow adipocytes profoundly enhances skeletal mass by activating BMP and EGF receptor signaling pathways.
- Targeting BMP receptor inhibitors combined with short-term EGF receptor activation presents a potential therapeutic strategy for increasing bone mass.
- This approach could be beneficial in preventing or reversing pathological bone loss conditions such as osteoporosis.
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