Osteocytogenesis: Roles of Physicochemical Factors, Collagen Cleavage, and Exogenous Molecules.

Osteocytes, the most abundant cell type in mammalian bone, are generally considered as the terminally differentiated cells of osteoblasts that are progressively self-buried or passively embedded in bone matrix. Emerging evidence reveals the essential functions of osteocytes in bone homeostasis and mechanotransduction. However, our knowledge on osteocytes, especially their formation, remains scarce. In this regard, the current review mainly focuses on several key factors that drive the osteocytic differentiation of osteoblasts, that is, osteocytogenesis. Available literature has demonstrated the involvement of physicochemical factors such as matrix composition, oxygen tension, and mechanical stress in the osteoblast-to-osteocyte transition. During cell migration and matrix remodeling, the matrix metalloproteinase-dependent collagen cleavage would play an "active" role in maturation and maintenance of the osteocytes. Besides, some in vitro methodologies are also established to induce the transformation of osteoblastic cell lines and primary mesenchymal cells to preosteocytes through cell transfection or addition of exogenous molecules (e.g., fibroblast growth factor-2, retinoic acid), which could potentiate the effort to form functional bone substitutes through elevated osteocytogenesis. Thus, advances of new technologies would enable comprehensive and in-depth understanding of osteocytes and their development, which in turn help promote the research on osteocyte biology and osteopathology.