IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway

Yongmei Wang, Zhiqiang Cheng, Hashem Z. Elalieh, Eiichiro Nakamura, Minh Thanh Nguyen, Susan MacKem, Thomas Clemens, Daniel D. Bikle, Wenhan Chang

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Abstract

Systemic derangements and perinatal death of generalized insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) knockout mice preclude definitive assessment of IGF-1R actions in growth-plate (GP) chondrocytes. We generated cartilage-specific Igf1r knockout (CartIgf1r-/-) mice to investigate local control of chondrocyte differentiation in the GP by this receptor. These mice died shortly after birth and showed disorganized chondrocyte columns, delayed ossification and vascular invasion, decreased cell proliferation, increased apoptosis, and increased expression of parathyroid hormone-related protein (Pthrp) RNA and protein in their GPs. The increased Pthrp expression in the knockout GPs likely was due to an increase in gene transcription, as determined by the increased activity of a LacZ reporter that was inserted downstream of the endogenous PTHrP promoter and bred into the knockout mice. To circumvent the early death of CartIgf1r -/- mice and investigate the role of IGF-1R during postnatal growth, we made tamoxifen (Tam)-inducible, cartilage-specific Igf1r knockout ( TamCartIgf1r-/-) mice. At 2 weeks of age and 7 to 8 days after Tam injection, the TamCartIgf1r-/- mice showed growth retardation with a disorganized GP, reduced chondrocyte proliferation, decreased type 2 collagen and Indian Hedgehog (Ihh) expression, but increased expression of PTHrP. Consistent with in vivo observations, in vitro knockout of the Igf1r gene by adenoviral expression of Cre recombinase suppressed cell proliferation, promoted apoptosis, and increased Pthrp expression. Our data indicate that the IGF-1R in chondrocytes controls cell growth, survival, and differentiation in embryonic and postnatal GPs in part by suppression of Pthrp expression.

Original languageEnglish (US)
Pages (from-to)1437-1446
Number of pages10
JournalJournal of Bone and Mineral Research
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 2011

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Keywords

  • CHONDROCYTE
  • GROWTH PLATE DEVELOPMENT
  • IGF-1 RECEPTOR
  • IHH
  • PTHRP

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Wang, Y., Cheng, Z., Elalieh, H. Z., Nakamura, E., Nguyen, M. T., MacKem, S., ... Chang, W. (2011). IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway. Journal of Bone and Mineral Research, 26(7), 1437-1446. https://doi.org/10.1002/jbmr.359