Cadherin-Mediated Cell–Cell Adhesion and Signaling in the Skeleton

Abstract

Direct cell-to-cell interactions via cell adhesion molecules, in particular cadherins, are critical for morphogenesis, tissue architecture, and cell sorting and differentiation. Partially overlapping, yet distinct roles of N-cadherin (cadherin-2) and cadherin-11 in the skeletal system have emerged from mouse genetics and in vitro studies. Both cadherins are important for precursor commitment to the osteogenic lineage, and genetic ablation of Cdh2 and Cdh11 results in skeletal growth defects and impaired bone formation. While Cdh11 defines the osteogenic lineage, persistence of Cdh2 in osteoblasts in vivo actually inhibits their terminal differentiation and impairs bone formation. The action of cadherins involves both cell-cell adhesion and interference with intracellular signaling, and in particular the Wnt/β-catenin pathway. Both cadherin-2 and cadherin-11 bind to β-catenin, thus modulating its cytoplasmic pools and transcriptional activity. Recent data demonstrate that cadherin-2 also interferes with Lrp5/6 signaling by sequestering these receptors in inactive pools via axin binding. These data extend the biologic action of cadherins in bone forming cells, and provide novel mechanisms for development of therapeutic strategies aimed at enhancing bone formation.

N-cadherin Restrains PTH Activation of Lrp6/β-catenin Signaling and Osteoanabolic Action

“…An alternative model of N‐cadherin interference with Wnt/β‐catenin has been proposed in osteoblasts, where N‐cadherin binds to Lrp5 or Lrp6 via axin. This interaction keeps either receptor tethered to N‐cadherin and promotes β‐catenin degradation . N‐cadherin/axin/Lrp5/6 interaction also prevents ERK1/2 and PI3K/Akt signaling, resulting in reduced osteoblast proliferation, differentiation, and survival .…”

“…This interaction keeps either receptor tethered to N-cadherin and promotes b-catenin degradation. (18,22) N-cadherin/axin/Lrp5/6 interaction also prevents ERK1/2 and PI3K/Akt signaling, resulting in reduced osteoblast proliferation, differentiation, and survival. (23) Conversely, disruption of this interaction allows activation of such signaling cascades, ultimately resulting in increased cell proliferation and differentiation.…”

CDH11 inhibits proliferation and invasion in head and neck cancer

“…CDH11 is usually expressed in mesenchymal cells and facilitates adhesion between these cells (23). CDH11 expression correlates with osteoblast-differentiation and promotes chondro-osteogenesis and inhibits adipogenesis (3,21). Consistent with an oncogenic role, CDH11, promotes invasion of prostate cancer cells and metastasis to bone (5,20).…”

Cadherin-11 endocytosis through binding to clathrin promotes cadherin-11-mediated migration in prostate cancer cells

“…E-cadherin (E-Cad; also known as CDH1) is mainly expressed in epithelial cells and plays a role in maintaining cellular contact in polarized epithelial cells (Nelson et al, 2013). Cadherin-11 (Cad11; also known as osteoblast cadherin), by contrast, is a mesenchymal cadherin that is mainly expressed in osteoblasts (Cheng et al, 1998;Marie et al, 2014;Okazaki et al, 1994).…”