Response of bipotential human marrow stromal cells to insulin-like growth factors: Effect on binding protein production, proliferation, and commitment to osteoblasts and adipocytes

Insulin-like growth factors (IGFs) are important regulators of the activity of mature osteoblasts, but their effects on osteoprogenitor cells in human bone marrow stroma are unclear. In this study, we assessed the effects of IGFs on a conditionally immortalized human marrow stromal cell line, hMS(3- 4), which has the ability to differentiate to either mature osteoblasts or adipocytes. hMS(3-4) cells expressed functional receptors for IGFs as well as specific IGF-binding proteins (IGFBP-3, -4, -5, and -6). IGF treatment o f hMS(3-4) cells did not alter IGFBP expression, but resulted in distinct p osttranslational modifications of secreted IGFBP-3 and IGFBP-4 proteins. IG F-I, IGF-II, and their receptor-activating analogs significantly increased by 2-fold the proliferation rate of the hMS(3-4) cells, but had a more comp lex effect on hMS(3-4) cell differentiation. Treatment with IGFs did not af fect gene expression of Cbfa1 or peroxisome proliferator-activated receptor gamma(2) (transcription factors involved in commitment to osteoblast and a dipocyte pathways, respectively), alkaline phosphatase, type I collagen, an d osteocalcin (markers of the osteoblast lineage), or lipoprotein lipase an d adipsin (markers of the adipocyte lineage) and did not change alkaline ph osphatase activity or type I collagen and osteocalcin protein relative to t otal protein production. In contrast, IGFs significantly increased type I c ollagen expression in differentiated hMS(3-4) cells as well as mature osteo blasts and promoted lipid accumulation in differentiated adipocytes. In sum mary, hMS(3-4) cells express essential components of the IGF system and res pond to IGF treatment with increased proliferation. There was no evidence f or IGFs directly modulating the commitment of hMS(3-4) cells to either oste oblast or adipocyte pathways, and their effects on differentiation within t hese lineages were dependent on the stage of cell maturation.