| First Author | Gomez GA | Year | 2022 |
| Journal | Elife | Volume | 11 |
| PubMed ID | 36342465 | Mgi Jnum | J:345122 |
| Mgi Id | MGI:7384074 | Doi | 10.7554/eLife.82810 |
| Citation | Gomez GA, et al. (2022) Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity. Elife 11:e82810 |
| abstractText | Pathological obesity and its complications are associated with an increased propensity for bone fractures. Humans with certain genetic polymorphisms at the kinase suppressor of ras2 (KSR2) locus develop severe early-onset obesity and type 2 diabetes. Both conditions are phenocopied in mice with <i>Ksr2</i> deleted, but whether this affects bone health remains unknown. Here we studied the bones of global <i>Ksr2</i> null mice and found that <i>Ksr2</i> negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene, <i>Ksr1</i>, was dispensable for bone homeostasis. Mechanistically, KSR2 regulates bone formation by influencing adipocyte differentiation at the expense of osteoblasts in the bone marrow. Compared with <i>Ksr2</i>'s known role as a regulator of feeding by its function in the hypothalamus, pair-feeding and osteoblast-specific conditional deletion of <i>Ksr2</i> reveals that <i>Ksr2</i> can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in the absence of <i>Ksr2</i>, bone strength, as well as fracture healing response, remains compromised in these mice. This study highlights the interrelationship between adiposity and bone health and provides mechanistic insights into how <i>Ksr2</i>, an adiposity and diabetic gene, regulates bone metabolism. |
