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The cyclin-dependent kinase inhibitor p57Kip2 mediates proliferative actions of PTHrP in chondrocytes
Helen E. MacLean, … , David Cobrinik, Henry M. Kronenberg
Helen E. MacLean, … , David Cobrinik, Henry M. Kronenberg
Published May 1, 2004
Citation Information: J Clin Invest. 2004;113(9):1334-1343. https://doi.org/10.1172/JCI21252.
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Article Bone Biology

The cyclin-dependent kinase inhibitor p57Kip2 mediates proliferative actions of PTHrP in chondrocytes

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Abstract

Parathyroid hormone–related peptide (PTHrP) is a positive regulator of chondrocyte proliferation during bone development. In embryonic mice lacking PTHrP, chondrocytes stop proliferating prematurely, with accelerated differentiation. Because the bone phenotype of mice lacking the cyclin-dependent kinase inhibitor p57Kip2 is the opposite of the PTHrP-null phenotype, we hypothesized that PTHrP’s proliferative actions in chondrocytes might be mediated by opposing p57. We generated p57/PTHrP-null embryos, which showed partial rescue of the PTHrP-null phenotype. There was reversal of the loss of proliferative chondrocytes in most bones, with reversal of the accelerated differentiation that occurs in the PTHrP-null phenotype. p57 mRNA and protein were upregulated in proliferative chondrocytes in the absence of PTHrP. Metatarsal culture studies confirmed the action of PTHrP to decrease p57 mRNA and protein levels in a model in which parathyroid hormone (PTH), used as an analog of PTHrP, increased chondrocyte proliferation rate and the length of the proliferative domain. PTH treatment of p57-null metatarsals had no effect on proliferation rate in round proliferative chondrocytes but still stimulated proliferation in columnar chondrocytes. These studies suggest that the effects of PTHrP on both the rate and extent of chondrocyte proliferation are mediated, at least in part, through suppression of p57 expression.

Authors

Helen E. MacLean, Jun Guo, Melissa C. Knight, Pumin Zhang, David Cobrinik, Henry M. Kronenberg

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Figure 1

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Normalization of PTHrP-null morphology by removal of p57. (A_D) Sections...
Normalization of PTHrP-null morphology by removal of p57. (A_D) Sections from control, p57+/_m, PTHrP_/_, and PTHrP_/_ ; p57+/_m littermates. (A) Morphology of E18.5 ulna. The p57-null ulna has a small increase in the number of proliferative chondrocytes (P), whereas the PTHrP-null ulna has almost complete loss of proliferative chondrocytes, with expanded hypertrophic chondrocytes (H) and expanded bone formation (indicated as Bo). The PTHrP/p57-null ulna shows normal morphology. Original magnification ∞10. (B) In situ hybridization of E18.5 ulna probed with PTH/PTHrP receptor (expressed in prehypertrophic and early-hypertrophic chondrocytes) and collagen X (expressed in hypertrophic chondrocytes). The PTHrP-null ulna shows virtually complete loss of proliferative and prehypertrophic layers, and these layers are restored in the PTHrP/p57-null ulna. Original magnification, ∞10. (C) Morphology of E18.5 vertebrae. The PTHrP-null vertebra has a reduction in proliferative chondrocytes and an expanded hypertrophic zone, and the PTHrP/p57-null vertebra shows restoration of normal morphology. Original magnification, ∞20. (D) Morphology of E18.5 tibia. The PTHrP-null tibia has a large reduction in the zone of columnar proliferative chondrocytes (CP), which is not normalized in the PTHrP/p57-null tibia. RP, round proliferative chondrocytes. Original magnification, ∞10.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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