Heparin Binding Epidermal Like Growth Factor-Mediated Marrow Adipocyte Ablation Induces Profound Bone Formation

ABSTRACT: Products of adipocytes control bone cells and may therefore lead to new anti-osteoporosis therapies. To address this issue we mated mice expressing the primate diphtheria toxin receptor (DTR), which is equivalent to Heparin Binding Epidermal Like Growth Factor (HB-EGF), under control of a Stop-flox cassette, to those expressing adiponectin-Cre (ADQ-Cre). Injected diphtheria toxin (DT) completely eliminates white and brown adipose tissue in these DTRADQ mice and ablates marrow adipocytes. Medullary bone of DTRADQ mice begins to accumulate, due to stimulated osteoblast recruitment and differentiation, within 4 days of injected DT. By 10-14 days of DT administration to DTRADQ mice, trabecular bone has increased 1000%. Two months after fat ablation, cortical thickness has markedly increased as has bone strength. To gain insight into the signaling events by which DT/DTRADQ adipocyte ablation promotes osteogenesis we performed RNAseq analysis of marrow prior to and after 1-3 days of DT injection. This exercise confirms ablation of marrow adipocytes, as adiponectin expression is markedly reduced while enhanced expression of Col1a1 and Col1a2 genes is in keeping with stimulated osteogenesis. RNAseq analysis also indicates that DT/DTRADQ-induced osteogenesis is mediated by the BMPR pathway. For example, there is suppressed genetic expression of the specific BMPR inhibitors, chordin-like1 (CHRDL1) and gremlin1 (GREM1). This adipocyte ablation-mediated increase in bone mass is due to cooperative activation of BMP and EGF receptor signaling as adipocyte-produced inhibitors are suppressed and downstream targets activated or expressed. Medicinal inhibition of either signaling pathway prevents induction of the osteosclerotic phenotype. DTR-induced post-natal osteogenesis does not represent the products of peripheral fat depots and is more likely due to those of marrow adipocytes. Thus, anabolic drugs activating both BMP and EGF receptor signaling may be a means of profoundly increasing bone mass and treating osteoporosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE154800 | GEO | 2020/11/06

REPOSITORIES: GEO