Cartilage disorders: potential therapeutic use of mesenchymal stem cells

Chondrogenesis is a well-orchestrated process driven by chondroprogenitors that undergo to condensation, proliferation and chondrocyte differentiation. Because cartilage lacks regenerative ability, treatments for cartilage diseases are primarily palliative. Adult bone marrow contains a reservoir of mesenchymal stem cells (MSC) with in vitro and in vivo potential of becoming cartilage. To optimize the potential therapeutic use of MSC in cartilage disorders, we need to understand the mechanisms by which growth factors determine their chondrogenic potential. Insulin-like growth factors (IGFs) play a central role in chondrogenesis as indicated by the severe growth failure observed in animals carrying null mutations of Igfs and Igf1R genes. We have found that IGF-I has potent chondrogenic effects in MSC. Effects are similar to transforming growth factor-Beta (TGF-Beta). Insulin-like growth factor binding protein-3 (IGFBP-3), well characterized as IGF carrier, has intrinsic bioactivities that are independent of IGF binding. IGFBP-3 levels are increased in degenerative cartilage diseases such as osteoarthritis. We have demonstrated that IGFBP-3 has IGF-independent growth inhibitory effects in chondroprogenitors. We now show that IGFBP-3 induces MSC apoptosis and antagonizes TGF-Beta chondroinductive effects in chondroprogenitors. Understanding IGF-I chondroinductive and IGFBP-3 chondroinhibitory effects would provide critical information to optimize the therapeutic use of MSC in cartilage disorders.