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.
Highlights
Severe loss of trabecular bone leads to osteopenia/osteoporosis, while a gain in trabecular bone mass is termed osteopetrosis
Given that the phenotypic rescue achieved by deleting receptor activator of nuclear factor kappa-B ligand (Rankl) in hypertrophic chondrocytes (HTCs) in the Ctnnb1LOFHTC mutant background was not 100%, and that βcatenin plays a role in periosteal osteoblast differentiation (Day et al, 2005; Hill et al, 2005), as well as in the light of recent publications demonstrating that HTC descendants can differentiate into osteoblasts (Yang et al, 2014a,b; Zhou et al, 2014), we addressed the question of whether chondrocyte-derived osteoblastogenesis is altered in Ctnnb1LOFHTC mutants
During the late phase of fetal development, remarkable remodeling processes occur in long bones – resorption of hypertrophic calcified cartilage, bone marrow cavity and trabecular bone formation
Summary
Severe loss of trabecular bone leads to osteopenia/osteoporosis, while a gain in trabecular bone mass is termed osteopetrosis. Terminally differentiated hypertrophic chondrocytes (HTCs) need to be turned over They undergo apoptosis and are actively removed by osteoclasts and chondroclasts (Bianco et al, 1998; Shapiro et al, 2005) or, alternatively, transdifferentiate into osteoblasts (Park et al, 2015; Yang et al, 2014a,b; Zhou et al, 2014).
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