Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP
Tatsuya Kobayashi, … , Andrew P. McMahon, Henry M. Kronenberg
Tatsuya Kobayashi, … , Andrew P. McMahon, Henry M. Kronenberg
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1734-1742. https://doi.org/10.1172/JCI24397.
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Research Article Bone biology

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

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.

Authors

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

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Figure 6

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Growth plate elongation was induced by Ihh overexpression without upregu...
Growth plate elongation was induced by Ihh overexpression without upregulation of PTHrP. PTHrP–/– mice were rescued by transgenic expression of caPPR to achieve Ihh-independent PPR signaling (c-PPR). Ihh was overexpressed in the growth plate with constantly maintained PPR signaling (c-PPR:Ihh-Bg). (A) H&E-stained growth plates of the distal tibia of caPPR:PTHrP–/– (c-PPR) and caPPR:PTHrP–/–:GAL4:UAS-Ihh (c-PPR:Ihh-Bg). Vertical lines represent the periarticular and columnar regions. (B) Alcian blue staining and in situ hybridization assay. Col2 expression was comparable between c-PPR and c-PPR:Ihh-Bg mice. Expansion of the columnar region in c-PPR:Ihh-Bg mice was confirmed by Bapx1 expression. Brackets indicate the proliferating zone (the periarticular and columnar regions). Dashed lines indicate bone contours.