Signal transduction and transcriptional regulation during mesenchymal cell differentiation

Although bone appears to be an apparently simple tissue, it is in reality a unique and very complex tissue composed of a variety of types of cells, including osteoblasts, osteoclasts, osteocytes, chondrocytes, adipocytes, immune cells, and hematopoietic cells [1]. Mesenchymal cells contribute to this diversity of bone tissue because mesenchymal cells are multipotent to differentiate into osteoblasts, chondrocytes, and adipocytes [2,3]. Differentiation processes of mesenchymal cells are harmoniously and dynamically controlled by specifi c signal transduction and transcription factors. In the past decade, transcription factors that specifi cally control the differentiation program of mesenchymal cells have been identifi ed. Genetic studies clearly demonstrate that Runx2 (Cbfa1/Pepb2aA) and Osterix (Sp7) are indispensable transcription factors for osteoblast development [4–6] (Fig. 1). Chondrocyte differentiation requires Sox family members in the early stage and Runx2 in the late stage [7–9] (Fig. 1). C/EBP family members and PPAR-γ play critical roles in adipocyte differentiation from mesenchymal cells [10,11] (Fig. 1). Moreover, recent studies have further advanced our understanding of the molecular basis by which these transcription factors regulate each differentiation program. In particular, biochemical studies have revealed how the expression and function of these transcription factors are controlled or modulated by coactivators, co-repressors, and other transcriptional regulators that assemble large complexes with the transcription factors. The functional roles of these transcription factors are also strictly regulated by signal transduction that links extracellular changes with the nucleus through the cytoplasm. Several cytokines and hormones such as bone morphogenetic protein (BMP), transforming growth factor-β (TGFβ), Wnt, hedgehog, fi broblast growth factors, estrogen, and androgen are involved in the regulation of mesenchymal cell differentiation by stimulating intracellular signaling pathways [1,9]. Specifi c intracellular signaling molecules are activated through phosphorylation, ubiquitination, protein– protein interaction, and conformational change in response to the ligand stimulation. The activated signaling molecules elicit the specifi c transcription factors by upregulating their transcriptional activity and/or translocation into the nucleus. These signaling pathways also engage in cross-talk, forming a complex network system. In this review article, we describe recent progress in describing molecular mechanisms that conduct the differentiation of mesenchymal cells into osteoblasts, chondrocytes, and adipocytes. First, we illustrate the role of BMP, TGF-β, Wnt, and Indian hedgehog (Ihh) signaling in mesenchymal cell differentiation. Second, we introduce the transcriptional regulation associated with the differentiation program of mesenchymal cells.