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Published on: December 3, 2016
IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway
Yongmei Wang1, Zhiqiang Cheng, Hashem Z Elalieh
1Endocrine Unit, University of California, Veterans Affairs Medical Center, San Francisco, CA, USA.
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 ((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.
Insights
The insulin-like growth factor 1 receptor (IGF-1R) in growth plate chondrocytes is crucial for bone growth. Its targeted deletion impairs chondrocyte proliferation, survival, and differentiation, impacting skeletal development.
Area of Science:
- Endocrinology
- Developmental Biology
- Skeletal Biology
Background:
- Generalized knockout of insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) leads to perinatal death, preventing detailed study of IGF-1R in growth plate chondrocytes.
- Previous research highlighted the systemic importance of IGF-1 signaling but lacked focus on local chondrocyte-specific functions.
Purpose of the Study:
- To investigate the specific role of IGF-1 receptor (IGF-1R) in regulating chondrocyte differentiation and function within the growth plate.
- To elucidate the mechanisms by which IGF-1R signaling controls chondrocyte behavior during embryonic and postnatal skeletal development.
Main Methods:
- Generation of cartilage-specific IGF-1R knockout mice ((Cart) Igf1r(-/-)) and tamoxifen-inducible versions ((TamCart) Igf1r(-/-)).
- Analysis of growth plate morphology, chondrocyte proliferation, apoptosis, ossification, and gene expression (Pthrp, Ihh, Col2a1).
- In vitro studies using adenoviral Cre recombinase to knock out Igf1r in chondrocytes.
Main Results:
- Cartilage-specific IGF-1R knockout resulted in perinatal lethality with severe growth plate disorganization, delayed ossification, and increased apoptosis.
- Inducible knockout in postnatal mice caused growth retardation, reduced chondrocyte proliferation, and altered expression of key developmental genes, including increased parathyroid hormone-related protein (Pthrp).
- In vitro studies confirmed that IGF-1R deficiency suppresses proliferation, promotes apoptosis, and upregulates Pthrp expression in chondrocytes.
Conclusions:
- IGF-1R signaling within growth plate chondrocytes is essential for regulating chondrocyte proliferation, survival, and differentiation.
- IGF-1R plays a critical role in controlling chondrocyte function, partly through the suppression of Pthrp expression.
- Targeted deletion of IGF-1R in chondrocytes significantly disrupts skeletal development, underscoring its localized importance.
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