Conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of chondrocytes to hypoxia

Abstract

Background Long bones of limbs are formed through endochondral bone formation, which depends on the coordinated development of growth plates. Our previous studies have demonstrated that dysfunction of mitogen-activated protein kinase 7 (MAPK7) can cause skeletal dysplasia. However, little is known about the role of MAPK7 in the regulation of proliferation and differentiation of chondrocytes during growth plate development. Results Ablation of MAPK7 expression in chondrocytes led to growth restriction, short limbs and bone mass loss in postnatal mice. Histological studies revealed that MAPK7 deficiency increased the apoptosis and decreased the proliferation of chondrocytes in the center of the proliferative layer, where the most highly hypoxic chondrocytes are located. Accordingly, hypertrophic differentiation markers were downregulated in the central hypertrophic layer, beneath the site where abnormal apoptosis was observed. Simultaneously, we demonstrated that hypoxic adaptation and hypoxia-induced activation of hypoxia-inducible factor 1 subunit α (HIF1α) were impaired when MAPK7 could not be activated normally in primary chondrocytes. Concomitantly, vascular invasion into epiphyseal cartilage was inhibited when Mapk7 was deleted. Conclusions We demonstrated that MAPK7 is necessary for maintaining proliferation, survival, and differentiation of chondrocytes during postnatal growth plate development, possibly through modulating HIF1α signaling for adaptation to hypoxia. These results indicate that MAPK7 signaling might be a target for treatment of chondrodysplasia.

The MEK5/ERK5 Pathway in Health and Disease

“…However, careful phenotypic analysis of the mesenchymal ERK5-deficient mice revealed that chondrogenesis was delayed, rather than suppressed, as evident by the lack of chondrocyte hypertrophy and the exclusive expression of COL2A1, a marker of non-hypertrophic chondrocytes, by the metatarsal chondrocytes [ 90 ]. Interestingly, the specific conditional deletion of Erk5 in the chondrocytes of postnatal mice also disturbed skeletogenesis, resulting in animals characterized by growth restriction, short limbs, and bone mass loss [ 94 ]. This phenotype was likewise attributed to impaired endochondral ossification and chondrocyte hypertrophy, as the mice showed decreased chondrocyte survival and proliferation in the hypoxic center of the proliferative layer [ 94 ].…”

“…Interestingly, the specific conditional deletion of Erk5 in the chondrocytes of postnatal mice also disturbed skeletogenesis, resulting in animals characterized by growth restriction, short limbs, and bone mass loss [ 94 ]. This phenotype was likewise attributed to impaired endochondral ossification and chondrocyte hypertrophy, as the mice showed decreased chondrocyte survival and proliferation in the hypoxic center of the proliferative layer [ 94 ]. Taken together, these reports imply a requirement for the proper timing and induction of chondrocyte hypertrophy rather than a general suppressive role of ERK5 in chondrogenesis.…”

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“…Yang et. al reported conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of chondrocytes to hypoxia [23] . The embryo development evaluation of Li et.…”