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IGF‐1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway
Author(s) -
Wang Yongmei,
Cheng Zhiqiang,
ElAlieh Hashem Z,
Nakamura Eiichiro,
Nguyen MinhThanh,
Mackem Susan,
Clemens Thomas L,
Bikle Daniel D,
Chang Wenhan
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.359
Subject(s) - chondrocyte , indian hedgehog , insulin like growth factor 1 receptor , knockout mouse , medicine , endocrinology , cyclopamine , parathyroid hormone related protein , conditional gene knockout , biology , endochondral ossification , growth factor , cartilage , receptor , signal transduction , microbiology and biotechnology , hedgehog , parathyroid hormone , anatomy , gene , phenotype , biochemistry , calcium
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 ( Cart Igf1r −/− ) 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 Cart Igf1r −/− mice and investigate the role of IGF‐1R during postnatal growth, we made tamoxifen (Tam)–inducible, cartilage‐specific Igf1r knockout ( TamCart Igf1r −/− ) mice. At 2 weeks of age and 7 to 8 days after Tam injection, the TamCart Igf1r −/− 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. © 2011 American Society for Bone and Mineral Research.