N-Cadherin/Wnt Interaction Controls Bone Marrow Mesenchymal Cell Fate and Bone Mass During Aging

Abstract

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.

Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism

“…However, knockdown of β-catenin led to severe cell death of LFS cells, confirming that β-catenin is necessary for homeostasis and viability of MSCs and OBs (SI Appendix, Fig. S3H) (55,56). Although it is widely accepted that hyper-WNT signaling is associated with oncogenicity in many cancers, our data support the idea that hyper-WNT is not always involved in osteosarcomagenesis.…”

“…The effects of SFRP2 on canonical WNT signaling are context dependent. Generally, SFRP2 suppresses WNT signaling by binding WNT ligands, thus preventing their binding to WNT receptors (30,55,56). However, SFRP2 has also been shown to activate WNT signaling at low concentrations or in certain cell types (35,(57)(58)(59).…”

Wnt/β-Catenin Signaling Mediates Osteoblast Differentiation Triggered by Peptide-induced α5β1 Integrin Priming in Mesenchymal Skeletal Cells

“…Three g of total RNA from each samples were reverse-transcribed using the a high-capacity cDNA reverse transcription kit (Applied Biosystems) in a total volume of 30 l at 37°C for 2 h. Relative mRNA levels were evaluated by quantitative PCR (LightCycler, Roche Applied Science) using a SYBR Green PCR kit (ABgene, Courtaboeuf, France) and specific primers (24,47,49). Signals were normalized to hypoxanthine phosphoribosyltransferase as an internal control.…”

PS1/γ‐Secretase‐Mediated Cadherin Cleavage Induces β‐Catenin Nuclear Translocation and Osteogenic Differentiation of Human Bone Marrow Stromal Cells

“…However, the molecular mechanisms that drive commitment and differentiation along the osteoblastic lineage are not completely understood. Because evidence showed that receptor-mediated canonical Wnt signaling would be just one of the players of a major and intricate signaling complex responsible for cell fate decision, in which cadherin molecules also participate [19, 20, 24], we focused on understanding how these signaling pathways influence downstream β -catenin signaling and osteogenic differentiation. We observed that Wnt3 was not able to stimulate β -catenin signaling, maintaining BMSCs in a proliferative state.…”