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印度刺猬因子刺激关节周围软骨细胞分化,以独立于甲状旁腺激素相关蛋白调节生长板长度。

Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP.

作者信息

Kobayashi Tatsuya, Soegiarto Desi W, Yang Yingzi, Lanske Beate, Schipani Ernestina, McMahon Andrew P, Kronenberg Henry M

机构信息

Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.

出版信息

J Clin Invest. 2005 Jul;115(7):1734-42. doi: 10.1172/JCI24397. Epub 2005 Jun 9.

Abstract

In the developing growth plate, periarticular chondrocytes proliferate, differentiate into columnar chondrocytes, and then further differentiate into postmitotic hypertrophic chondrocytes. Parathyroid hormone-related (PTH-related) protein (PTHrP), regulated by Indian hedgehog (Ihh), prevents premature hypertrophic differentiation, thereby maintaining the length of columns. Ihh regulates cartilage development through PTHrP-independent pathways as well. Here we show that Ihh stimulates differentiation of periarticular to columnar chondrocytes (periarticular chondrocyte differentiation) and thereby regulates the length of columns independently of PTHrP. Mosaic ablation of the PTH/PTHrP receptor in the growth plate caused upregulation of Ihh action, PTHrP upregulation, acceleration of periarticular chondrocyte differentiation, and elongation of the columnar region. Decreasing Ihh action in these mice reduced elongation of columns, whereas decreasing PTHrP showed only a modest effect on column length. Overexpression of Ihh caused PTHrP upregulation, elongation of columns, and acceleration of periarticular chondrocyte differentiation. PTHrP heterozygosity in this model had a minimal effect on the elongation of columns. Moreover, the elongation of columns and stimulation of periarticular chondrocyte differentiation in these models were still observed when PTHrP signaling was maintained so that it remained constant. These results demonstrate that Ihh acts on periarticular chondrocytes to stimulate their differentiation, thereby regulating the columnar cell mass independently of PTHrP.

摘要

在发育中的生长板中,关节周围软骨细胞增殖,分化为柱状软骨细胞,然后进一步分化为有丝分裂后的肥大软骨细胞。由印度刺猬因子(Ihh)调控的甲状旁腺激素相关蛋白(PTHrP)可防止过早的肥大分化,从而维持柱状结构的长度。Ihh也通过不依赖PTHrP的途径调节软骨发育。在此我们表明,Ihh刺激关节周围软骨细胞向柱状软骨细胞分化(关节周围软骨细胞分化),从而独立于PTHrP调节柱状结构的长度。生长板中PTH/PTHrP受体的镶嵌性消融导致Ihh作用上调、PTHrP上调、关节周围软骨细胞分化加速以及柱状区域延长。在这些小鼠中降低Ihh作用可减少柱状结构的延长,而降低PTHrP对柱状长度仅产生适度影响。Ihh的过表达导致PTHrP上调、柱状结构延长以及关节周围软骨细胞分化加速。在此模型中PTHrP杂合性对柱状结构的延长影响极小。此外,当PTHrP信号维持恒定不变时,在这些模型中仍可观察到柱状结构的延长以及关节周围软骨细胞分化的刺激。这些结果表明,Ihh作用于关节周围软骨细胞以刺激其分化,并由此独立于PTHrP调节柱状细胞群。

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