The molecular genetics of bone formation: implications for therapeutic interventions in bone disorders

Skeletal biology is a complex process involving the developmental commitment and differentiation of chondrocytes and osteoblasts which produce and mineralize cartilage and bone matrix during growth and postnatal life. Several genes are involved in controlling osteogenesis by acting on target cells in a very complex manner. Manipulation of genes in mice and studies of genetic mutations affecting the skeleton in humans have enabled the assessment of the role of transcription factors, bone matrix proteins and regulatory factors involved in the control of chondrocyte and osteoblast differentiation, and have considerably improved our understanding of the bone formation process. Clinical studies and gene polymorphism analyses suggest that the variable expression of particular genes may be linked to clinical osteoporosis. A major challenge in the future will be to develop molecularly targeted approaches to stimulating bone formation and increasing bone mass. The use of mouse strain models and transgenic animals with variable bone density may be useful to identify genetic determinants of bone mass which may serve as a basis for drug discovery and development. On the other hand, the availability of gene microarrays and other emerging genomic techniques are promising tools to identify genes that are distinctly expressed in health and disease. These technologies may also serve to test the mechanisms of action of drugs aimed at increasing bone formation. Genetic studies of the molecular signaling pathways involved in normal and pathological osteogenesis may also help to identify genes that could be targeted for therapeutic intervention. Candidate approaches include selective gene transfection in target cells and the use of drugs acting on gene promoters to selectively enhance gene expression in osteoblasts. The development of these strategies is expected not only to bring new insight into the molecular mechanisms that govern bone formation in normal and pathological situations but, in the long term, may also result in the identification of novel molecular targets for therapeutic interventions for bone formation disorders.