KDM6B preferentially promotes bone formation over resorption to facilitate postnatal bone mass accrual through collagen triple helix repeat containing 1-mediated PKCδ/MAPKs signaling

Feb 17, 2025Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

KDM6B helps build more bone than it breaks down after birth by activating collagen-related signaling

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Abstract

Adult mice lacking Kdm6b specifically in mesenchyme and osteoprogenitor cells exhibited decreased cancellous bone mass.

The absence of Kdm6b resulted in reduced numbers of both osteoblasts and osteoclasts.
Increased marrow adipocytes were observed in the Kdm6b-deficient mice.
Bone formation and resorption were repressed in mice lacking Kdm6b.
Kdm6b-deficient bone marrow stromal cells showed impaired ability to differentiate into bone-forming cells.
RNA sequencing revealed downregulation of CTHRC1 and a lower ratio of RANKL to osteoprotegerin in the mutant mice.
KDM6B appears to promote osteoblast differentiation by epigenetically regulating CTHRC1 expression.

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Lysine demethylase 6B (KDM6B) plays a role in regulating osteoblast differentiation and fetal bone ossification. Nevertheless, its involvement in regulating postnatal bone homeostasis and bone mass accrual remains unclear. In this study, we generated mice lacking Kdm6b gene specifically in mesenchyme and osteoprogenitor cells using a conditional strategy. The adult mice of both mutant strains had decreased cancellous bone mass. The absence of Kdm6b in mesenchyme led to decreased numbers of osteoblasts and osteoclasts, increased marrow adipocytes, as well as repressed bone formation and resorption. Additionally, Kdm6b-deficient bone marrow stromal cells (BMSCs) displayed impaired osteogenic differentiation and exerted an inhibitory effect on osteoclastogenesis. RNA-seq combined with gene expression analysis uncovered downregulation of collagen triple helix repeat containing 1 (CTHRC1) and a lower RANKL/osteoprotegerin (OPG) ratio in BMSCs of the mutant mice. Further mechanistic explorations demonstrated that KDM6B epigenetically upregulated CTHRC1 expression by removing the repressive H3K27me3 mark from its promoter, thereby triggering PKCδ/MAPKs signaling to facilitate osteoblast differentiation. CTHRC1 was able to mitigate the dysregulated osteogenic and adipogenic differentiation induced by Kdm6b deficiency. This study provides evidence that KDM6B regulates postnatal bone homeostasis through balancing osteoblast and osteoclast differentiation. Given its predominant promotion of osteoblastic bone formation over osteoclastic bone resorption, KDM6B tends to promote postnatal bone mass accrual.

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KDM6B preferentially promotes bone formation over resorption to facilitate postnatal bone mass accrual through collagen triple helix repeat containing 1-mediated PKCδ/MAPKs signaling

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