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. 2023 Mar:168:116650.
doi: 10.1016/j.bone.2022.116650. Epub 2022 Dec 28.

Colon epithelial cell-specific Bmal1 deletion impairs bone formation in mice

Frank C Ko  1 , Sarah B Jochum  2 , Brittany M Wilson  3 , Amal Adra  3 , Nikhil Patel  3 , Hoomin Lee  3 , Sherry Wilber  4 , Maliha Shaikh  4 , Christopher Forsyth  5 , Ali Keshavarzian  5 , Garth R Swanson  5 , D Rick Sumner  6
Affiliations

Colon epithelial cell-specific Bmal1 deletion impairs bone formation in mice

Frank C Ko et al. Bone. 2023 Mar.

Abstract

The circadian clock system regulates multiple metabolic processes, including bone metabolism. Previous studies have demonstrated that both central and peripheral circadian signaling regulate skeletal growth and homeostasis in mice. Disruption in central circadian rhythms has been associated with a decline in bone mineral density in humans and the global and osteoblast-specific disruption of clock genes in bone tissue leads to lower bone mass in mice. Gut physiology is highly sensitive to circadian disruption. Since the gut is also known to affect bone remodeling, we sought to test the hypothesis that circadian signaling disruption in colon epithelial cells affects bone. We therefore assessed structural, functional, and cellular properties of bone in 8 week old Ts4-Cre and Ts4-Cre;Bmal1fl/fl (cBmalKO) mice, where the clock gene Bmal1 is deleted in colon epithelial cells. Axial and appendicular trabecular bone volume was significantly lower in cBmalKO compared to Ts4-Cre 8-week old mice in a sex-dependent fashion, with male but not female mice showing the phenotype. Similarly, the whole bone mechanical properties were deteriorated in cBmalKO male mice. The tissue level mechanisms involved suppressed bone formation with normal resorption, as evidenced by serum markers and dynamic histomorphometry. Our studies demonstrate that colon epithelial cell-specific deletion of Bmal1 leads to failure to acquire trabecular and cortical bone in male mice.

Keywords: Bmal1; Bone remodeling; Circadian rhythm; Gut-bone axis.

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Figures

Figure 1.
Figure 1.
Microarchitecture properties of distal metaphyseal femur (A) and L5 vertebra (B). μCT images from male Ts4-Cre and cBmalKO mice. Fem = femoral; L5 = L5 vertebral; BV/TV = bone volume/total volume; Tb.Th = trabecular thickness; Tb.Sp = trabecular separation. Data presented as Mean ± SD
Figure 2.
Figure 2.
Biomechanical properties of femoral diaphysis and L5 vertebrae in Ts4-Cre and cBmalKO mice. Fem = femoral; L5 = L5 vertebral. Data presented as Mean ± SD
Figure 3.
Figure 3.
Serum bone remodeling markers (A) and static and dynamic histomorphometry (B). Trichrome and fluorochrome images from male Ts4-Cre and cBmalKO mice. Ob.S/BS = osteoblast surface/bone surface; Oc.S/BS = osteoclast surface/bone surface; MAR = mineral apposition rate; BFR/BS = bone formation rate/bone surface. Data presented as Mean ± SD
See this image and copyright information in PMC

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