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¹ Vanderbilt University School of Medicine, Department of Pediatrics, T-0107 Medical Center North, Nashville, Tennessee, USA
² Santo Spirito Hospital, Pescara, Italy
³ Vanderbilt University School of Medicine, Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA
⁴ University of Chieti, Department of Pediatrics, Chieti, Italy

(Requests for offprints should be addressed to A Spagnoli, Department of Pediatrics and Cancer Biology, Vanderbilt University School of Medicine, T-0107 Medical Center North, Nashville, Tennessee 37232-2579, USA; Email: anna.spagnoli{at}vanderbilt.edu)

Cartilage formation is driven by mesenchymal chondroprogenitor cells (MCCs) that proliferate and differentiate into chondrocytes. The molecular mechanisms by which growth factors regulate MCC fate are not well defined. Insulin-like growth factor binding protein-3 (IGFBP-3) has intrinsic bioactivity that is independent of IGF binding. We previously reported that IGFBP-3 has IGF-independent antiproliferative and apoptotic effects in MCCs, and requires STAT-1 activation to mediate its apoptotic effect. Transforming growth factor-ß (TGF-ß) is a key chondroinductive growth factor. The objective of the study is to define the interactions between IGFBP-3 and TGF-ß in MCC growth and their intracellular signaling pathways. We used the RCJ3•1C5•18 mesenchymal chondrogenic cells that without biochemical or oncogenic transformation progress in culture from MCCs to differentiated chondrocytes. Cell proliferation was assessed in MCCs treated with IGFBP-3 or transfected with IGFBP-3, in the presence or absence of TGF-ß. To demonstrate that IGFBP-3 effects were IGF-independent an IGFBP-3 analog that lacks IGF binding was used (GGG-IGFBP-3). To determine the functional roles of the TGF-ß-mediated signaling and the STAT-1 pathway, cells were either stably transfected with a dominant negative TGF-ß type II receptor (MCC-DNTßRII) or treated with a STAT-1 morpholino antisense oligonucleotide. We found that in MCCs, TGF-ß antagonized the antiproliferative effect of IGFBP-3. IGFBP-3 increased the cyclin-dependent kinase inhibitor p21 expression and this effect was abolished by TGF-ß. Furthermore, TGF-ß inhibited STAT-1 phosphorylation induced by IGFBP-3. Similarly to TGF-ß, STAT-1 antisense oligonucleotide inhibited the IGFBP-3 antiproliferative action. Although TGF-ß in MCC-DNTßRII lacked Smad-mediated signaling, it persistently antagonized the IGFBP-3 antiproliferative action. However, TGF-ß even in MCC-DNTßRII cells induced ERK1/2 phosphorylation, and treatment with MEK inhibitor, UO126, inhibited the antagonistic effects of TGF-ß on IGFBP-3. Furthermore, UO126 blocked the TGF-ß inhibition of STAT-1 phosphorylation induced by IGFBP-3. Collectively, these results demonstrate cross-talk between the IGFBP-3-dependent STAT-1 signaling and the TGF-ß-dependent ERK pathway that regulates MCC proliferation.

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