Osteoblast dysfunctions in bone diseases: from cellular and molecular mechanisms to therapeutic strategies

Abstract

Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.

Fig. 1

Mechanisms underlying the osteoblast dysfunctions in skeletal aging and potential therapeutic strategies to attenuate these osteoblast abnormalities. The defective bone formation associated with aging is characterized by preferential differentiation of mesenchymal stromal cells (MSCs) into adipocytes instead of pre-osteoblasts, reduced osteoblast differentiation and function and increased osteoblast and octeocyte death. These abnormalities result from alterations in local signaling factors, senescence mechanisms and epigenetic alterations of genes controlling osteoblastogenesis (a). Potential therapeutic strategies to reduce the osteoblast dysfunctions and improve bone formation in the aging skeleton include promoting anabolic signaling pathways, inhibiting negative regulators of bone formation, and attenuating senescence and epigenetic mechanisms in cells of the osteoblast lineage (b)

Fig. 2

Osteoblast dysfunctions and potential targeted therapies in primary bone tumors. In primary bone tumors, genomic instability, aberrations in tumor suppressor genes, oncogenes and epigenetic deregulation of key transcription factors result in the transformation of osteoblast precursor cells into tumor cells which exhibit deregulated cell proliferation, defective terminal osteoblast differentiation and reduced cell apoptosis. These abnormalities can be specifically targeted to restore normal bone formation, as indicated