Contrasting effects of <i>Ksr2</i>, an obesity gene, on trabecular bone volume and bone marrow adiposity.

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.