SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice
SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice
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DOI：
10.1242/dev.072652
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发表时间：
2012-03-15
期刊：
影响因子：
4.6
通讯作者：
Tsumaki, Noriyuki
中科院分区：
文献类型：
--
作者：
Sasagawa, Satoru;Takemori, Hiroshi;Tsumaki, Noriyuki
软骨细胞肥大对于软骨内骨化至关重要，但这一过程的机制尚不完全清楚。我们报告盐诱导激酶 3 (SIK3) 缺陷会导致小鼠软骨细胞肥大的严重抑制。 SIK3缺陷的小鼠随着年龄的增长表现出侏儒症，而在胚胎发生过程中体型不受影响。解剖学和组织学分析显示，SIK3 缺陷小鼠的生长板和四肢关节软骨区域显着扩张，胸骨、肋骨和脊柱中软骨细胞积聚，颅骨形成受损。 SIK3缺陷小鼠骨骼组织的主要表型位于E14.5时的肱骨，其中软骨细胞肥大明显延迟。直到E18.5，软骨细胞肥大被严重阻断，增殖的软骨细胞占据了肱骨内部。与 SIK3 缺陷小鼠的软骨细胞肥大受损一致，在胚胎发育中的骨骼和出生后小鼠的生长板中的肥大前和肥大软骨细胞的细胞质中检测到天然 SIK3 表达。 HDAC4是软骨细胞肥大的关键抑制因子，在SIK3缺陷的软骨细胞中保留在细胞核中，但在野生型肥大软骨细胞中位于细胞质中。分子和细胞分析表明，SIK3是将HDAC4锚定在细胞质中所必需的，从而释放MEF2C（软骨细胞肥大的关键促进因子）免受细胞核中HDAC4的抑制。 SIK3 的软骨细胞特异性过度表达诱导成年期生长板的闭合，并且通过肱骨中的转基因 SIK3 表达来挽救 SIK3 缺陷的软骨表型。这些结果表明 SIK3 在骨骼形成和生长板维持过程中促进软骨细胞肥大中发挥重要作用。
Chondrocyte hypertrophy is crucial for endochondral ossification, but the mechanism underlying this process is not fully understood. We report that salt-inducible kinase 3 (SIK3) deficiency causes severe inhibition of chondrocyte hypertrophy in mice. SIK3-deficient mice showed dwarfism as they aged, whereas body size was unaffected during embryogenesis. Anatomical and histological analyses revealed marked expansion of the growth plate and articular cartilage regions in the limbs, accumulation of chondrocytes in the sternum, ribs and spine, and impaired skull bone formation in SIK3-deficient mice. The primary phenotype in the skeletal tissue of SIK3-deficient mice was in the humerus at E14.5, where chondrocyte hypertrophy was markedly delayed. Chondrocyte hypertrophy was severely blocked until E18.5, and the proliferative chondrocytes occupied the inside of the humerus. Consistent with impaired chondrocyte hypertrophy in SIK3-deficient mice, native SIK3 expression was detected in the cytoplasm of prehypertrophic and hypertrophic chondrocytes in developing bones in embryos and in the growth plates in postnatal mice. HDAC4, a crucial repressor of chondrocyte hypertrophy, remained in the nuclei in SIK3-deficient chondrocytes, but was localized in the cytoplasm in wild-type hypertrophic chondrocytes. Molecular and cellular analyses demonstrated that SIK3 was required for anchoring HDAC4 in the cytoplasm, thereby releasing MEF2C, a crucial facilitator of chondrocyte hypertrophy, from suppression by HDAC4 in nuclei. Chondrocyte-specific overexpression of SIK3 induced closure of growth plates in adulthood, and the SIK3-deficient cartilage phenotype was rescued by transgenic SIK3 expression in the humerus. These results demonstrate an essential role for SIK3 in facilitating chondrocyte hypertrophy during skeletogenesis and growth plate maintenance.