Abstract
The developing long bone is a model of endochondral ossification that displays the morphological layers of chondrocytes toward the ossification center of the diaphysis. Indian hedgehog (Ihh), a member of the hedgehog family of secreted molecules, regulates chondrocyte proliferation and differentiation, as well as osteoblast differentiation, through the process of endochondral ossification. Here, we report that the basic helix-loop-helix transcription factor Hand1, which is expressed in the cartilage primordia, is involved in proper osteogenesis of the bone collar via its control of Ihh production. Genetic overexpression of Hand1 in the osteochondral progenitors resulted in prenatal hypoplastic or aplastic ossification in the diaphyses, mimicking an Ihh loss-of-function phenotype. Ihh expression was downregulated in femur epiphyses of Hand1-overexpressing mice. We also confirmed that Hand1 downregulated Ihh gene expression in vitro by inhibiting Runx2 transactivation of the Ihh proximal promoter. These results demonstrate that Hand1 in chondrocytes regulates endochondral ossification, at least in part through the Runx2-Ihh axis.
Highlights
The vertebrate skeleton develops through two tightly controlled processes: intramembranous ossification and endochondral ossification
The process of ossification begins in two locations; the primary ossification is located in the center of the future diaphysis and the secondary ossification is located in the center of the epiphysis
Twist2 promoter-driven Cre expression is detected in the chondrocytes of the growth plate cartilage and the osteoblasts in the perichondrium, periosteum, and endosteum [11]
Summary
The vertebrate skeleton develops through two tightly controlled processes: intramembranous ossification and endochondral ossification. Twist2 promoter-driven Cre expression is detected in the chondrocytes of the growth plate cartilage and the osteoblasts in the perichondrium, periosteum, and endosteum [11]. These findings suggest that Hand1 overexpression may interfere with the commitment of limb mesenchyme cells to the cartilage fate and/or control the development of endochondral ossification.
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