MaineHealth Institute for Research, Scarborough, ME 04074, United States.
West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
J Bone Miner Res. 2024 Aug 21;39(8):1188-1199. doi: 10.1093/jbmr/zjae104.
Calorie restriction (CR) can lead to weight loss and decreased substrate availability for bone cells. Ultimately, this can lead to impaired peak bone acquisition in children and adolescence and bone loss in adults. But the mechanisms that drive diet-induced bone loss in humans are not well characterized. To explore those in greater detail, we examined the impact of 30% CR for 4 and 8 wk in both male and female 8-wk-old C57BL/6 J mice. Body composition, areal bone mineral density (aBMD), skeletal microarchitecture by micro-CT, histomorphometric parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. After 8 wk, CR mice lost weight and exhibited lower femoral and whole-body aBMD vs ad libitum (AL) mice. By micro-CT, CR mice had lower cortical bone area fraction vs AL mice, but males had preserved trabecular bone parameters and females showed increased bone volume fraction compared to AL mice. Histomorphometric analysis revealed that CR mice had a profound suppression in trabecular as well as endocortical and periosteal bone formation in addition to reduced bone resorption compared to AL mice. Bone marrow adipose tissue was significantly increased in CR mice. In vitro, the pace of adipogenesis in bone marrow stem cells was greatly accelerated with higher markers of adipocyte differentiation and more oil red O staining, whereas osteogenic differentiation was reduced. qRT-PCR and western blotting suggested that the expression of Wnt16 and the canonical β-catenin pathway was compromised during CR. In sum, CR causes impaired peak cortical bone mass due to a profound suppression in bone remodeling. The increase in marrow adipocytes in vitro and in vivo is related to both progenitor recruitment and adipogenesis in the face of nutrient insufficiency. Long-term CR may lead to lower bone mass principally in the cortical envelope, possibly due to impaired Wnt signaling.
热量限制（CR）可导致体重减轻和骨细胞的底物可用性降低。最终，这可能导致儿童和青少年的峰值骨量获取受损以及成年人的骨量流失。但是，驱动人类饮食诱导性骨丢失的机制尚未得到很好的描述。为了更详细地探讨这些机制，我们研究了雄性和雌性 8 周龄 C57BL/6J 小鼠分别进行 4 周和 8 周 30%CR 的影响。检测了身体成分、面积骨矿物质密度（aBMD）、通过 micro-CT 的骨骼微结构、组织形态计量学参数以及成骨细胞和脂肪细胞分化的体外轨迹。8 周后，CR 小鼠体重减轻，股骨和全身 aBMD 低于自由进食（AL）小鼠。通过 micro-CT，CR 小鼠的皮质骨面积分数低于 AL 小鼠，但雄性保留了小梁骨参数，而雌性与 AL 小鼠相比，骨体积分数增加。组织形态计量学分析表明，CR 小鼠的小梁骨以及内皮质和骨膜骨形成受到严重抑制，骨吸收减少。与 AL 小鼠相比，CR 小鼠的骨髓脂肪组织显著增加。体外，骨髓干细胞的脂肪生成速度大大加快，脂肪细胞分化的标志物更高，油红 O 染色更多，而成骨分化减少。qRT-PCR 和 Western blot 表明，在 CR 期间 Wnt16 和经典 β-连环蛋白途径的表达受到损害。总之，CR 导致峰值皮质骨量减少，原因是骨重塑受到严重抑制。体外和体内骨髓脂肪细胞的增加与营养不足时祖细胞募集和脂肪生成有关。长期 CR 可能导致皮质包络骨量减少，主要是由于 Wnt 信号受损。
