Changes in insulin-like growth factor-binding protein expression and secretion during the proliferation, differentiation, and mineralization of primary cultures of rat osteoblasts.

Insulin-like growth factor-I (IGF-I) and IGF-II are secreted by the bone-forming osteoblast and have been shown to promote mitogenesis and/or differentiation of several of the cells involved in adult bone remodeling. The biological actions of the IGFs are modulated in a cell-specific manner by IGF-binding proteins (IGFBPs). All six IGFBPs are expressed by osteoblasts. Both in vitro and in vivo, osteoblasts progress through a developmental sequence from committed precursors to mature differentiated cells that form a mineralized extracellular matrix. We have examined IGFBP expression and secretion by rat calvarial cultures, a model system of osteoblast development, to correlate changes with the developmental stage. Differential expression and secretion of IGFBPs during osteoblast development were observed. Maximal IGFBP-2 and -5 messenger RNA (mRNA) expression occurred in proliferating preosteoblasts, whereas mature osteoblasts showed maximal expression of IGFBP-3, -4, and -6. Rat osteoblasts did not express IGFBP-1. Increases in IGFBP-2, -3, and -4 secretion lagged behind corresponding mRNA increases by 3-6 days. Whereas mRNA levels declined as the cultures mineralized, IGFBP secretion continued to increase. Inhibition of osteoblast proliferation, which promotes differentiation, resulted in an IGFBP secretory pattern that was consistent with that seen with mature cells. Conversely, an IGFBP secretion pattern characteristic of proliferating cells could be maintained for weeks if differentiation was inhibited. We conclude that the developmental stage of the osteoblast is an important determinant of IGFBP secretion. We propose that hormonal regulation that alters the developmental stage may secondarily affect IGFBP expression or secretion.