title: IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway.
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.
authors.affiliation: Endocrine Unit, University of California, Veterans Affairs Medical Center, San Francisco, CA, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Hashem Z
authors.initials: HZ
authors.lastname: Elalieh
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nakamura
authors.forename: Minh-Thanh
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Susan
authors.initials: S
authors.lastname: Mackem
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001846:Bone Development; D001842:Bone and Bones / Q000196:embryology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006132:Growth Plate / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; C514061:ihh protein, mouse; D017526:Receptor, IGF Type 1