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 2

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Ihh overexpression in the growth plate causes growth plate expansion and...
Ihh overexpression in the growth plate causes growth plate expansion and acceleration of periarticular chondrocyte differentiation. (A) Alcian blue staining showed that Ihh overexpression in the growth plate by the Col2-GAL4:UAS-cIhh bigenic system (Ihh-Bg) caused longitudinal elongation of the growth plate of the E17.5 distal tibia. Col2-GAL4 single-transgenic mice were used as the control (Ctrl). (B) The distal growth plate of the tibia was analyzed due to the knee joint fusion of Ihh-Bg. (C) Ptc and PTHrP upregulation in the periarticular region of the Ihh-Bg growth plate (arrowheads). (D and E) Cell number was reduced despite increased proliferation in the periarticular region of Ihh-Bg mice. Three mice in each group were analyzed. Sections representing the mid–cross-plane of the tibia were selected for BrdU staining (D) and cell number counting (D and E). Cell number in each region was counted on BrdU/H&E-stained sections and expressed as BrdU-positive cells/total cells in the periarticular (P) or columnar (C) regions of each section. Red and magenta dotted lines indicate the periarticular and columnar regions, respectively. (E) Despite an approximately 50% increase in BrdU-labeling ratio in the periarticular region of Ihh-Bg mice, the cell number was smaller than that in control mice by approximately 30%. In contrast, the cell number in the columnar (D) region of Ihh-Bg mice was approximately 30% greater, whereas the BrdU labeling ratio was similar to that of control mice. n = 3 in each group; *P < 0.05.