Regulatory Mechanism of Osteoblast Differentiation and Bone Formation.

Abstract

IntroductionOsteoblasts , chondrocytes , myoblasts , and bone marrow stromal cells including adipocytes are believed to derive from common mesenchymal progenitors ( 1-7 ) called pluripotent mesenchymal stem cells (5-7). These progenitors exhibit specific phenotypes depending on the maturational stages during their differentiation pro− cesses. In the case of osteoblasts, they express phenotypic characteristics such as high alkaline phosphatase (ALP) activity, and synthesize collagenous and non-collagenous bone matrix proteins including osteocalcin (4). Formation of mineralized bones is the most important function of osteoblasts . This phenotypic expression is regulated by various hormones including parathyroid hormone (PTH) (8,9), 1α, 25 (OH)2D3] (10) and estrogen (11,12). Various local factors produced by osteoblasts also regulate their own differentiation in a paracrine and/or an autocrine fashion (4). To investigate the roles of these hormones and local factors in osteoblast differentiation, various osteoblastic cell lines have been successfully established (13)(14)(15)(16)(17). Experiments using these in vitro assay systems have contributed to understanding the regulation of osteoblast differentiation by various hormones and local factors.In the process of cell differentiation , many transcription factors are involved in the regulatory mechanism of each cell type, and cell lineage-specific transcription factors play crucial roles in determining each cell fate. These transcription factors have been identified in several cell lineages such as myoblasts and adipocytes: MyoD family in myoblasts ( 18 ) and PPARγ-2 in adipocytes (19). Recently, three research groups independently reported that Cbfa 1, which belongs to the runt-domain gene family , is an essential transcription factor for osteoblast differentiation and bone formation (20)(21)(22).This review describes recent advances regarding the mechanism of osteoblast differentiation and its regulation by the systemic factors and local factors including Correspondence: Akira Yamaguchi, Department of Oral Pathology, Nagasaki University School of Dentistry, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan Phone/Fax +81-95-849-7644 E-mail akirayam@net.nagasaki-u.ac.jp estrogen, parathyroid hormone ( PTH) , bone morphogenetic proteins (BMPs), hedgehogs, and the transcription factor Cbfa1. I. Differentiation of osteoblastsOsteoprogenitors are present in both skeletal and extraskeletal tissues in the post-natal state. In the skeletal tissues, osteoprogenitors locate in bone marrow and the periosteum. Friedenstein and colleagues first demonstrated that bone marrow cells harvested from confluent in vitro cultures of marrow cells retained the ability to form bones when cultured in vivo within diffusion chambers (23). They also showed that single cell-derived fibroblastic colonies, which have been called colony forming units-fibroblastic (CFU-F), retained osteogenic potential. Intermittent injection of PTH increased the number of CFU-F, which explain a potential mechanism involve...