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 Ksr2’s 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding: This work was supported by grants from National Institutes of Health (R01 AR048139 and R21 AG062866) and U.S. Department of Veterans Affairs (101 BX005263 and Ik6 BX005381) awarded to SM. SM is a recipient of Senior Research Career Scientist Award U.S. Department of Veterans Affairs.
Disclosures: David R. Powell was employed by Lexicon Pharmaceuticals, Inc, at the time some of these studies were performed and may own common stock or have been granted stock options. The authors report no other conflicts of interest in this work.
Gustavo A. Gomez: Gustavo.Gomez2{at}va.gov, Charles H. Rundle: Charles.Rundle{at}va.gov, Weirong Xing: Weirong.Xing{at}va.gov, Chandrasekhar Kesavan: Chandrasekhar.Kesavan{at}va.gov, Sheila Pourteymoor: Sheila.Pourteymoor{at}va.gov, Robert E. Lewis: rlewis{at}unmc.edu, David R. Powell: DPowell{at}lexpharma.com, Subburaman Mohan: Subburaman.Mohan{at}va.gov