Conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of
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Cell & Bioscience Open Access
RESEARCH
Conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of chondrocytes to hypoxia Xiaoming Yang1,3†, Dongmei Zhong2†, Wenjie Gao4, Zhiheng Liao1,3, Yuyu Chen1,3, Shun Zhang1,3, Hang Zhou1,3, Peiqiang Su1,3* and Caixia Xu2*
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 mitogenactivated 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. Keywords: MAPK7, Chondrocytes, Growth plate development, Hypoxia, HIF1α
*Correspondence: [email protected]; [email protected] † Xiaoming Yang and Dongmei Zhong contributed equally to this work 1 The Department of Orthopedics, The First Affiliated Hospital, Sun Yatsen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong, People’s Republic of China 2 Research Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong, People’s Republic of China Full list of author information is available at the end of the article
Introduction All long bones of limbs are formed through endochondral bone formation, where the growth plate, which consists of chondrocytes, is gradually replaced by mineralized bone [1]. Chondrocytes within growth plates originate from the chondrogenic differentiation of mesenchymal stem cells (MSCs) within embryonic limb buds during embryonic development [2, 3]. Endochondral bone formation depends on the highly coordinated development of growth plates, where chondrocytes within the growth plate continuously unde
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