β-catenin activity in late hypertrophic chondrocytes locally orchestrates osteoblastogenesis and osteoclastogenesis

Abstract

Trabecular bone formation is the last step in endochondral ossification. This remodeling process of cartilage into bone involves blood vessel invasion and removal of hypertrophic chondrocytes (HTCs) by chondroclasts and osteoclasts. Periosteal- and chondrocyte-derived osteoprogenitors utilize the leftover mineralized HTC matrix as a scaffold for primary spongiosa formation. Here, we show genetically that β-catenin (encoded by Ctnnb1), a key component of the canonical Wnt pathway, orchestrates this remodeling process at multiple levels. Conditional inactivation or stabilization of β-catenin in HTCs by a Col10a1-Cre line locally modulated osteoclastogenesis by altering the Rankl:Opg ratio in HTCs. Lack of β-catenin resulted in a severe decrease of trabecular bone in the embryonic long bones. Gain of β-catenin activity interfered with removal of late HTCs and bone marrow formation, leading to a continuous mineralized hypertrophic core in the embryo and resulting in an osteopetrotic-like phenotype in adult mice. Furthermore, β-catenin activity in late HTCs is required for chondrocyte-derived osteoblastogenesis at the chondro-osseous junction. The latter contributes to the severe trabecular bone phenotype in mutants lacking β-catenin activity in HTCs.

β-catenin Signaling Regulates Cell Fate Decisions at the Transition Zone of the Chondro-Osseous Junction During Fracture Healing

“…Numerous genetic lineage tracing studies have demonstrated that chondrocytes directly contribute to endochondral bone formation by transforming into osteoblasts. 8,[12][13][14][15][16][17] This has been shown in the contexts of bone development, postnatal growth, and fracture repair with an array of reporter systems (Col10-Cre, Col2-Cre ERT2 , Aggrecan-Cre ERT2 , eGFP-and β-galactosidase-labelled tissue transplants). 8,[12][13][14][15][16][17] We advanced this here and show that chondrocytes are also likely precursors of progenitor cells that line the newly formed bone.…”

Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease

“…Interestingly, activation of Wnt signaling by stabilization of β‐catenin results in inhibition of preadipocyte differentiation into mature adipocytes via reducing PPARγ expression, raising the possibility that Wnt signaling determines the cell fate of osteoblastic and adipogenetic progenitors, priming them toward osteoblasts. Recent studies have provided in vivo evidence that removal of β‐catenin in the osteoblastic ( Osx‐Cre ) or chondrogenic ( Col10a1‐Cre ) lineages causes low bone mass and increased bone marrow adiposity . Although the HC origin of adipocytes in the Col10a1‐Cre ; β‐catenin conditional null mutants was not established, it is possible that a cell fate shift from the HCs‐derived osteoblasts into adipocytes may partly contribute to the observed phenotypes.…”

Role of Wnt/β-catenin pathway in inducing autophagy and apoptosis in multiple myeloma cells

“…Previous studies have demonstrated that the activation of the Wnt/β-catenin signaling pathway has a critical role in both osteoblastogenesis and osteoclastogenesis (4,5). In addition, aberrant activation of the Wnt/β-catenin signaling pathway has been shown to be involved in numerous types of cancers (6,7).…”