title: A novel insulin-like growth factor (IGF)-independent role for IGF binding protein-3 in mesenchymal chondroprogenitor cell apoptosis.
abstract: Chondrogenesis results from the condensation of mesenchymal chondroprogenitor cells (MCC) that proliferate and differentiate into chondrocytes. We have previously shown that IGF binding protein (IGFBP)-3 has an IGF-independent antiproliferative effect in MCC. The current study evaluates the IGF-independent apoptotic effect of IGFBP-3 on MCC to modulate chondrocyte differentiation. We employed the RCJ3.1C5.18 chondrogenic cell line, which in culture progresses from MCC to differentiated chondrocytes; cells do not express IGFs or IGFBP-3. We also used IGFBP-3 mutants with decreased (I56 substituted to G56; L80 and L81 to G80G81) or abolished binding for IGFs (I56, L80, and L81 to G56G80G81). MCC transfected with IGFBP-3 detached, changed their phenotype, and underwent apoptosis. A maximal IGFBP-3 apoptotic effect was observed 24 h after transfection (463 +/- 73% of controls; P < 0.001). Remarkably, IGFBP-3 mutants had similar effects, demonstrating that the IGFBP-3 apoptotic action was clearly IGF independent. In addition, treatment with IGFBP-3 in serum-free conditions resulted in a significant increase of apoptosis (173 +/- 23% of controls; P < 0.05). Moreover, this apoptotic effect was selective for MCC, resulting in a selective reduction of chondrocytic nodules and a significant decrease in type II collagen expression and proteoglycan synthesis. In summary, we have identified a novel IGF-independent role for IGFBP-3 in the modulation of chondrocyte differentiation.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2579, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Longobardi
authors.forename: Monica
authors.initials: M
authors.lastname: Torello
authors.forename: Caroline
authors.initials: C
authors.lastname: Buckway
authors.forename: Lynda
authors.initials: L
authors.lastname: O'Rear
authors.forename: William A
authors.initials: WA
authors.lastname: Horton
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Charles T
authors.initials: CT
authors.lastname: Roberts
authors.forename: Francesco
authors.initials: F
authors.lastname: Chiarelli
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.forename: Anna
authors.initials: A
authors.lastname: Spagnoli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology / Q000502:physiology*; D013002:Somatomedins / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D013002:Somatomedins