Contrasting effects of Ksr2, an obesity gene, on trabecular bone volume and bone marrow adiposity
Curation statements for this article:-
Curated by eLife
eLife Assessment:
This is a very valuable study that describes the bone phenotype and mechanism of the action of the obesity gene Ksr2. That there is a site-selective bone phenotype is interesting as is the identification of KSR2 as an actionable target.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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. 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 the 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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eLife Assessment:
This is a very valuable study that describes the bone phenotype and mechanism of the action of the obesity gene Ksr2. That there is a site-selective bone phenotype is interesting as is the identification of KSR2 as an actionable target.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
The authors report the bone phenotype of the global Ksr2 null mouse and find that Ksr2 negatively regulates cortical (femur) but not cancellous (vertebra) bone mass. The paralog Ksr1, in contrast, is not required for bone mass regulation. They also show that KSR2 regulates bone formation by shifting adipocyte differentiation at the expense of osteoblasts in the bone marrow. This is a very well-performed study with clear results that have been appropriately interpreted and discussed. The overall impact of understanding the mechanistic switch between the adipocyte and osteoblast is significant. The identification of an actionable target that is validated through prior human studies is also of importance. Weaknesses are minor.
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Reviewer #2 (Public Review):
This is an extensive and thorough investigation into the effects of Ksr2 as well as Ksr1 in bone marrow function with regards to adipocity and osteoblast and osteoclast function. The majority of the work is largely descriptive of several phenotypes of Ksr1 and Ksr2 knock-out mice as well as a conditional osteoblast-specific Ksr2 deletion to demonstrate effects of the gene directly in osteoblasts exclusive of the effects that Lsr2 deletion in the hypothalamus would have had on body physiology. Because of the descriptive nature, which is well documented, there is not a lot of negative criticism of the current study. One area of weakness, however, would be the underutilization of the conditional knockout, which would have allowed for superior ex vivo studies compared to the whole body knockout. Likewise, the …
Reviewer #2 (Public Review):
This is an extensive and thorough investigation into the effects of Ksr2 as well as Ksr1 in bone marrow function with regards to adipocity and osteoblast and osteoclast function. The majority of the work is largely descriptive of several phenotypes of Ksr1 and Ksr2 knock-out mice as well as a conditional osteoblast-specific Ksr2 deletion to demonstrate effects of the gene directly in osteoblasts exclusive of the effects that Lsr2 deletion in the hypothalamus would have had on body physiology. Because of the descriptive nature, which is well documented, there is not a lot of negative criticism of the current study. One area of weakness, however, would be the underutilization of the conditional knockout, which would have allowed for superior ex vivo studies compared to the whole body knockout. Likewise, the authors start to dissect the underlying physiology of how Ksr2 interacts within osteoblasts to exert its effects, however, those studies involving mTor are not as exhaustive as the rest of the manuscript. Overall this is a thorough study that adds to the overall understanding of the role of Ksr2 in obesity and bone physiology.
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