Inserm UMR-1132, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
J Cell Physiol. 2014 Nov;229(11):1765-75. doi: 10.1002/jcp.24629.
Age-related bone loss is characterized by reduced osteoblastogenesis and excessive bone marrow adipogenesis. The mechanisms governing bone marrow mesenchymal stromal cell (BMSC) differentiation into adipocytes or osteoblasts during aging are unknown. We show here that overexpressing N-cadherin (Cadh2) in osteoblasts increased BMSC adipocyte differentiation and reduced osteoblast differentiation in young transgenic (Tg) mice whereas this phenotype was fully reversed with aging. The reversed phenotype with age was associated with enhanced Wnt5a and Wnt10b expression in osteoblasts and a concomitant increase in BMSC osteogenic differentiation. Consistent with this mechanism, conditioned media from young wild type osteoblasts inhibited adipogenesis and promoted osteoblast differentiation in BMSC from old Cadh2 Tg mice, and this response was abolished by Wnt5a and Wnt10b silencing. Transplantation of BMSC from old Cadh2 Tg mice into young Tg recipients increased Wnt5a and Wnt10b expression and rescued BMSC osteogenic differentiation. In senescent osteopenic mice, blocking the CADH2-Wnt interaction using an antagonist peptide increased Wnt5a and Wnt10b expression, bone formation, and bone mass. The data indicate that Cadh2/Wnt interaction in osteoblasts regulates BMSC lineage determination, bone formation, and bone mass and suggest a therapeutic target for promoting bone formation in the aging skeleton.
与年龄相关的骨质流失的特征是成骨细胞生成减少和骨髓脂肪生成过多。目前尚不清楚控制骨髓间充质基质细胞（BMSC）在衰老过程中分化为脂肪细胞或成骨细胞的机制。我们在这里表明，在年轻的转基因（Tg）小鼠中过表达成骨细胞中的 N-钙黏蛋白（Cadh2）会增加 BMSC 脂肪细胞分化并减少成骨细胞分化，而这种表型在衰老时完全逆转。随着年龄的增长，这种表型的逆转与成骨细胞中 Wnt5a 和 Wnt10b 表达的增强以及 BMSC 成骨分化的相应增加有关。与该机制一致，来自年轻野生型成骨细胞的条件培养基抑制 BMSC 中的脂肪生成并促进来自年老 Cadh2 Tg 小鼠的成骨细胞分化，而 Wnt5a 和 Wnt10b 的沉默则消除了这种反应。将来自年老 Cadh2 Tg 小鼠的 BMSC 移植到年轻的 Tg 受体中会增加 Wnt5a 和 Wnt10b 的表达并挽救 BMSC 的成骨分化。在衰老性骨质疏松症小鼠中，使用拮抗剂肽阻断 CADH2-Wnt 相互作用会增加 Wnt5a 和 Wnt10b 的表达、骨形成和骨量。数据表明，成骨细胞中的 Cadh2/Wnt 相互作用调节 BMSC 谱系决定、骨形成和骨量，并为促进衰老骨骼中的骨形成提供了一个治疗靶点。
