Osteogenic differentiation is a sophisticated and tightly regulated biological process. In response to specific stimuli, mesenchymal stem cells (MSCs) differentiate into osteoblasts; the bone-forming cells, through a multistep process characterized by four major phases: commitment toward the osteogenic lineage, osteoprogenitor cells proliferation; osteoblast maturation, and bone matrix mineralization.
Induction of the differentiation process and progression through the different steps are by a complex network of cytokines, hormones, and growth factors that modulates expression and activity of transcription factors and other bone-related proteins. Among growth factors involved in osteogenic regulation; bone morphogenetic proteins (BMPs) play a role of paramount relevance in inducing bone and cartilage development.
The growth factor-beta
BMPs belong to the transforming growth factor-beta superfamily and signal through two types of transmembrane serine-threonine kinase receptors; type I and type II [BMP receptor type I (BMPR-I) and BMP receptor type II BMPR-II]; which, upon ligand binding, activate downstream signaling pathways such as Smad1/5/8 and MAPK pathways. BMPs locally synthesized accumulate in the extracellular matrix and play a critical role in both inducing commitment of MSCs toward the osteogenic lineage and enhancing the activity of mature osteoblasts.
Despite intensive investigation, our knowledge of the molecular mechanisms driving MSCs differentiation toward the osteogenic lineage is still incomplete. A better comprehension of this biological process is of crucial importance since bone-related pathologies; constitute an increasing health care burden in industrialized countries and require safer and more effective therapeutic strategies.
Regenerative medicine applications
MSCs represent a promising cell source for regenerative medicine applications and an excellent model to study pathways relevant in osteoblast differentiation. These cells, indeed, present several advantages over other adult stem cells: they can extensively expand in vitro; they are immune-privileged and able to produce trophic factors and several anti-inflammatory and immunomodulatory cytokines.
Therefore, the identification of the molecular bases of osteogenic differentiation is mandatory; to regulate and optimize the process and to fully exploit MSC therapeutic potential. The present report focuses on the characterization of ObI-1, a novel putative transcriptional regulator of osteogenic differentiation. ObI-1 belongs to the family of KRAB/zinc-finger transcription factors, the largest family of transcriptional regulators in mammals.
These transcription factors are present exclusively in tetrapod vertebrates and are involved in the regulation of several biological processes; such as cell proliferation and differentiation (including osteogenic), apoptosis, and neoplastic transformation. The role of ObI-1 as a transcription factor is also supports by its nuclear localization. Our finding is also consistent with a previous article that describes the same gene as a transcriptional repressor in mouse gonads