MOLECULAR TO PHARMACOLOGICAL CONTROL OF OSTEOBLAST PROLIFERATION AND DIFFERENTIATION

Control of osteoblast growth and development can be characterized from receptor mediated events to nuclear messengers controlling gene trans cription. From this analysis it is possible to formulate a model to ex plain the reciprocal relationship between growth and differentiation a s well as differential cytokine modulation of osteoblast function. Cen tral to this model are putative tissue specific transcriptional switch es (possibly of the bHLH gene superfamily) that may repress proliferat ion and permit the regulation of mature osteoblast phenotypic characte ristics. This model proposes that in post-mitotic differentiated osteo blasts, tissue specific transcription factors determine the capacity t o express osteoblastic characteristic, whereas receptor activated sign alling cascades, namely, cAMP/protein kinase A, receptor serine/threon ine kinase, and vitamin D receptor-dependent pathways, regulate mature osteoblast-specific gene expression. Activated differentiation switch es also may feedback to transcriptionally repress proliferation. Conve rsely, in preosteoblasts, in which differentiation switches are turned off, distinct signalling cascades involving tyrosine kinases, PKC, an d calcium/calmodulin regulate proliferation. Proliferating preosteobla sts also exhibit negative modulation of maturation either through inac tivation of putative tissue-specific transcription factors and/or thro ugh AP-1 dependent phenotype suppression of genes expressed in mature osteoblast. Thus, the final outcome of transcriptional regulation of o steoblast function results from complex interactions between signallin g pathways and permissive differentiating transcription factors. Thoug h many aspects of this model remain speculative and require confirmati on, it serves as a useful conceptual framework to further investigate the differential control of osteoblast proliferation and differentiati on that may lead to improved pharmacologic ways to manipulate bone for mation in vivo. (C) 1994 Wiley-Liss, Inc.