Conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of chondrocytes to hypoxia
Conditional ablation of MAPK7 expression in chondrocytes impairs endochondral bone formation in limbs and adaptation of chondrocytes to hypoxia
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DOI：
10.1186/s13578-020-00462-8
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发表时间：
2020-09
影响因子：
7.5
通讯作者：
Xiaoming Yang;Dongmei Zhong;Wenjie Gao;Zhiheng Liao;Yuyu Chen;Shun Zhang;Hang Zhou;Peiqiang Su;Caixia Xu
中科院分区：
文献类型：
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作者：
Xiaoming Yang;Dongmei Zhong;Wenjie Gao;Zhiheng Liao;Yuyu Chen;Shun Zhang;Hang Zhou;Peiqiang Su;Caixia Xu
研究背景四肢长骨是通过软骨内成骨形成的，而软骨内成骨依赖于生长板的协调发育。我们以前的研究表明，丝裂原活化蛋白激酶7（MAPK 7）功能障碍可导致骨骼发育不良。然而，鲜为人知的是，在生长板development.ResultsAblation的MAPK7在软骨细胞的增殖和分化的调节中的作用，导致生长受限，短肢和骨质疏松的出生后小鼠在软骨细胞中的MAPK7的表达。组织学研究表明，MAPK7缺陷增加了增殖层中心的软骨细胞的凋亡并降低了增殖，其中最高度缺氧的软骨细胞位于该中心。相应地，肥大分化标志物在中央肥大层中下调，在观察到异常凋亡的部位下方。同时，我们证明了当原代软骨细胞中MAPK7不能正常激活时，缺氧适应和缺氧诱导的缺氧诱导因子1亚基α（HIF 1 α）的激活受到损害。同时，血管侵入骺软骨被抑制whenMapk7被deleted.ConclusionsWe证明，MAPK7是必要的，以维持增殖，生存和分化的软骨细胞在出生后生长板的发展，可能通过调节HIF 1 α信号适应缺氧。这些结果表明MAPK7信号传导可能是治疗软骨发育不良的靶点。
BackgroundLong 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.ResultsAblation 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 whenMapk7was deleted.ConclusionsWe 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.