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bioRxiv · 10.1101/2022.08.21.504689

Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity

Gomez, G. A.·Rundle, C.·Xing, W.·Kesavan, C.·Pourteymoor, S.·Lewis, R. E.·Powell, D. R.·Mohan, S.
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Abstract

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 (T2D). Both conditions are phenocopied in mice with Ksr2 deleted, but whether this affects bone health remains unknown. Here we studied the bones of global Ksr2 null mice and found that Ksr2 negatively regulates femoral, but not vertebral, bone mass in two genetic backgrounds, while the paralogous gene, Ksr1, 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 Ksr2s known role as a regulator of feeding by its function in the hypothalamus, pair feeding and osteoblast-specific conditional deletion of Ksr2 reveals that Ksr2 can regulate bone formation autonomously. Despite the gains in appendicular bone mass observed in absence of Ksr2, 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 Ksr2, an adiposity and diabetic gene, regulates bone metabolism.

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Gomez, G. A., Rundle, C., Xing, W., Kesavan, C., Pourteymoor, S., Lewis, R. E., Powell, D. R., Mohan, S.. 2022-08-21. Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity. https://doi.org/10.1101/2022.08.21.504689

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