Canonical Wnt/β-Catenin Signaling Prevents Osteoblasts from Differentiating into Chondrocytes

Abstract

Osteoblasts and chondrocytes are involved in building up the vertebrate skeleton and are thought to differentiate from a common mesenchymal precursor, the osteo-chondroprogenitor. Although numerous transcription factors involved in chondrocyte and osteoblast differentiation have been identified, little is known about the signals controlling lineage decisions of the two cell types. Here, we show by conditionally deleting beta-catenin in limb and head mesenchyme that beta-catenin is required for osteoblast lineage differentiation. Osteoblast precursors lacking beta-catenin are blocked in differentiation and develop into chondrocytes instead. In vitro experiments demonstrate that this is a cell-autonomous function of beta-catenin in an osteoblast precursor. Furthermore, detailed in vivo and in vitro loss- and gain-of-function analyses reveal that beta-catenin activity is necessary and sufficient to repress the differentiation of mesenchymal cells into Runx2- and Sox9-positive skeletal precursors. Thus, canonical Wnt/beta-catenin signaling is essential for skeletal lineage differentiation, preventing transdifferentiation of osteoblastic cells into chondrocytes.

Mechanisms of digit formation: Human malformation syndromes tell the story

“…This can be mainly attributed to the inhibitory effect of signals emanating from the ectoderm, because ectoderm removal leads to ectopic chondrogenesis (Hurle and Ganan, 1986). The dorsal and ventral limb ectoderm is a source for several members of the Wnt family of diffusible signaling molecules and there is substantial evidence suggesting that a gradient of Wnt/b-catenin signaling within the limb mesoderm has a key role in restricting chondrogenesis to the limb core (Hill et al, 2005(Hill et al, , 2006ten Berge et al, 2008).…”

“…limb bud (from E10.5 to E12.5 in the mouse), chondrogenesis appears to be restricted to the core of the limb bud due to suppressive ectodermal Wnt/bcatenin and Fgf signaling (Hill et al, 2005;ten Berge et al, 2008), with condensation apparently following a ''passive'' mechanism. Chondrogenesis is positively regulated by BMP signaling from the mesenchyme by means of BMPs 2, 4, and 7 and Gdf5.…”

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

“…(6) Conditional deletion of b-catenin, the central molecule of canonical Wnt signaling, in limb and head mesenchyme during early embryonic development has resulted in arrest of osteogenesis and lack of mature osteoblasts. (7)(8)(9) In absence of b-catenin, osteochondroprogenitors differentiate into chondrocytes instead of osteoblasts. (7)(8)(9) A key role of Wnt signaling in embryonic skeletal development has recently been confirmed in mesenchyme Lrp5 and Lrp6 double-deficient mutants.…”

“…(7)(8)(9) In absence of b-catenin, osteochondroprogenitors differentiate into chondrocytes instead of osteoblasts. (7)(8)(9) A key role of Wnt signaling in embryonic skeletal development has recently been confirmed in mesenchyme Lrp5 and Lrp6 double-deficient mutants. (10) The phenotype of the double-deficient embryo closely resembles that of the b-catenindeficient mutant.…”

Bone mass is inversely proportional to Dkk1 levels in mice

“…The absence of β-catenin in early skeletal progenitor cells causes osteoblast precursors to become chondrocytes [13][14][15]. Inactivation of β-catenin in committed osteoblast progenitors prevented the expression of osteoblast-specific genes, indicating that β-catenin is also essential for osteoblast differentiation [15,16].…”