The developmental stages of osteoblast growth and differentiation exhibit selective responses of genes to growth factors (TGF beta 1) and hormones (vitamin D and glucocorticoids).
Osteoblasts in vitro undergo a developmental sequence of growth and differentiation characterized by a stage-specific expression of cell growth and bone-related genes. Our studies show that contributions to development of the osteoblast phenotype include: (1) the down-regulation of proliferation, (2) biosynthesis and organization of type 1 collagen extracellular matrix, and (3) mineralization of this matrix. Hormones and growth factors added to isolated osteoblasts during the initial proliferation period can dramatically alter the subsequent program of developmental stages of differentiation. Studies are presented that demonstrate alterations in gene expression in response to: (1) transforming growth factor beta (TGF beta 1), that prevents differentiation of the cells and their ability to form bony tissue-like nodules; (2) glucocorticoids, which induce and accelerate development of the bone-cell phenotype; and (3) the active metabolite of vitamin D, 1,25(OH)2D3, which results in both inhibitory and stimulatory effects of the hormone on growth and differentiation--effects that are dependent upon the differentiated state of the osteoblast. Thus, in the presence of these physiological mediators of bone-cell phenotype development, many of the growth and differentiation relationships operative in osteoblasts are modified or abrogated, precluding expression of the structural and functional properties of mature bone cells and tissue. These findings have significant implications for use of hormones or growth factors in the treatment of disorders where bone is involved.
Lian
J B
JB
Department of Cell Biology, University of Massachusetts Medical Center, Worcester, MA 01655.
Stein
G S
GS
D000818:Animals; D001483:Base Sequence; D016723:Bone Remodeling / Q000235:genetics; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics*; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D003907:Dexamethasone / Q000494:pharmacology; D005109:Extracellular Matrix; D005938:Glucocorticoids / Q000494:pharmacology; D006133:Growth Substances / Q000502:physiology*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016348:Osseointegration / Q000235:genetics; D010006:Osteoblasts / Q000187:drug effects* / Q000502:physiology; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010012:Osteogenesis / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation
D005938:Glucocorticoids; D006133:Growth Substances; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; D003907:Dexamethasone; D004247:DNA; D002117:Calcitriol