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A Novel Insulin-Like Growth Factor (IGF)-Independent Role for IGF Binding Protein-3 in Mesenchymal Chondroprogenitor Cell Apoptosis

Department of Pediatrics (L.L., A.S., L.O.), Vanderbilt University Medical Center, Nashville, Tennessee 37232-2579; Research Center (M.T., W.A.H.), Shriners Hospital for Children, and Department of Pediatrics (C.B., V.H., C.T.R., R.G.R.), Oregon Health & Science University, Portland, Oregon 97201; and Department of Pediatrics (F.C.), University of Chieti, 66013 Chieti, Italy

Address all correspondence and requests for reprints to: Anna Spagnoli, Department of Pediatrics, Vanderbilt University Medical Center, T-0107 Medical Center North, Nashville, Tennessee 37232-2579. E-mail: anna.spagnoli{at}mcmail.vanderbilt.edu.

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.

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