Expression of Hoxa2 in cells entering chondrogenesis impairs overall cartilage development

Abstract

Vertebrate Hox genes act as developmental architects by patterning embryonic structures like axial skeletal elements, limbs, brainstem territories, or neural crest derivatives. While active during the patterning steps of development, these genes turn out to be down-regulated in specific differentiation programs like that leading to chondrogenesis. To investigate why chondrocyte differentiation is correlated to the silencing of a Hox gene, we generated transgenic mice allowing Cre-mediated conditional misexpression of Hoxa2 and induced this gene in Collagen 2 alpha 1-expressing cells committed to enter chondrogenesis. Persistent Hoxa2 expression in chondrogenic cells resulted in overall chondrodysplasia with delayed cartilage hypertrophy, mineralization, and ossification but without proliferation defects. The absence of skeletal patterning anomaly and the regular migration of precursor cells indicated that the condensation step of chondrogenesis was normal. In contrast, closer examination at the differentiation step showed severely impaired chondrocyte differentiation. In addition, this inhibition affected structures independently of their embryonic origin. In conclusion, for the first time here, by a cell-type specific misexpression, we precisely uncoupled the patterning function of Hoxa2 from its involvement in regulating differentiation programs per se and demonstrate that Hoxa2 displays an anti-chondrogenic activity that is distinct from its patterning function.

Ezh2 is required for neural crest-derived cartilage and bone formation

“…For instance, Hoxa2, which is overexpressed in BA1 cells of Ezh2 cko embryos, is a well-known inhibitor of intramembranous bone formation from BAs, and when overexpressed in the Hox-negative domain of avian embryos impairs formation of the facial skeleton (Couly et al, 1998;Creuzet et al, 2002;Kanzler et al, 1998). Massip and colleagues have shown that ectopic expression of Hoxa2 in chondrocytes results in impaired differentiation, as demonstrated by the lack of Col2a1, and prevents cartilage formation (Massip et al, 2007). In BA2, Hoxa2 is a promoter of the hyoid fate of mesenchymal CNCCs and restricts the chondrogenic domains that arise during endochondral ossification (Pasqualetti et al, 2000).…”

Knockdown of Hoxa11 In Vivo in the Uterosacral Ligament and Uterus of Mice Results in Altered Collagen and Matrix Metalloproteinase Activity1

“…It is thought that HOX regulation of collagen subtypes imparts regional differences in the mechanical properties of tissues. Further, HOXA family genes have been implicated in the regulation of expression of key proteins involved in dynamic tissue and ECM remodeling, including the MMPs and TIMPs, which inhibit MMP activity [21][22][23][24]. Tissue remodeling is a continuous process, and a balance between matrix synthesis and breakdown is necessary to maintain the integrity of the genital tissue.…”

Molecular Study of a Hoxa2 Gain-of-Function in Chondrogenesis: A Model of Idiopathic Proportionate Short Stature

“…In 2007, Massip and colleagues generated a transgenic mouse model which induced Hoxa2 gene expression in a Cre-mediated way [3]. Crossing these mice with Col2a1-Cre transgenics [24] provoked an ectopic and persistent expression of Hoxa2 in every Col2a1 expressing cell, i.e.…”

“…This reduction impacted the endochondral ossification process, resulting in a postnatal growth defect mimicking human PSS [3,4]. Indeed, whereas the transgenic mice were similar in size to the control animals at birth, they featured a significant but harmonious shortening of both the trunk and the appendicular skeleton as early as the day four.…”