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. 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. 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.

中文翻译：

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软骨细胞中 MAPK7 表达的条件消融会损害四肢的软骨内骨形成和软骨细胞对缺氧的适应。

四肢长骨是通过软骨内成骨形成的，这依赖于生长板的协调发育。我们之前的研究表明，丝裂原活化蛋白激酶 7 (MAPK7) 的功能障碍可导致骨骼发育不良。然而，关于 MAPK7 在生长板发育过程中调节软骨细胞增殖和分化的作用知之甚少。软骨细胞中 MAPK7 表达的消融导致出生后小鼠的生长受限、四肢短和骨量减少。组织学研究表明，MAPK7 缺乏增加了细胞凋亡并减少了增殖层中心的软骨细胞增殖，该中心是最缺氧的软骨细胞所在的位置。因此，肥大分化标志物在中央肥大层中下调，在观察到异常细胞凋亡的部位下方。同时，我们证明当 MAPK7 在原代软骨细胞中不能正常激活时，缺氧适应和缺氧诱导的缺氧诱导因子 1 亚基 α (HIF1α) 的激活受到损害。同时，当 Mapk7 被删除时，血管对骨骺软骨的侵袭受到抑制。我们证明了 MAPK7 对于在出生后生长板发育过程中维持软骨细胞的增殖、存活和分化是必需的，可能通过调节 HIF1α 信号传导以适应缺氧。这些结果表明 MAPK7 信号可能是治疗软骨发育不良的靶点。同时，我们证明当 MAPK7 在原代软骨细胞中不能正常激活时，缺氧适应和缺氧诱导的缺氧诱导因子 1 亚基 α (HIF1α) 的激活受到损害。同时，当 Mapk7 被删除时，血管对骨骺软骨的侵袭受到抑制。我们证明了 MAPK7 对于在出生后生长板发育过程中维持软骨细胞的增殖、存活和分化是必需的，可能通过调节 HIF1α 信号传导以适应缺氧。这些结果表明 MAPK7 信号可能是治疗软骨发育不良的靶点。同时，我们证明当 MAPK7 在原代软骨细胞中不能正常激活时，缺氧适应和缺氧诱导的缺氧诱导因子 1 亚基 α (HIF1α) 的激活受到损害。同时，当 Mapk7 被删除时，血管对骨骺软骨的侵袭受到抑制。我们证明了 MAPK7 对于在出生后生长板发育过程中维持软骨细胞的增殖、存活和分化是必需的，可能通过调节 HIF1α 信号传导以适应缺氧。这些结果表明 MAPK7 信号可能是治疗软骨发育不良的靶点。同时，当 Mapk7 被删除时，血管对骨骺软骨的侵袭受到抑制。我们证明了 MAPK7 对于在出生后生长板发育过程中维持软骨细胞的增殖、存活和分化是必需的，可能通过调节 HIF1α 信号传导以适应缺氧。这些结果表明 MAPK7 信号可能是治疗软骨发育不良的靶点。同时，当 Mapk7 被删除时，血管对骨骺软骨的侵袭受到抑制。我们证明了 MAPK7 对于在出生后生长板发育过程中维持软骨细胞的增殖、存活和分化是必需的，可能通过调节 HIF1α 信号传导以适应缺氧。这些结果表明 MAPK7 信号可能是治疗软骨发育不良的靶点。