Regulation of Osteoblast Differentiation Mediated by Bone Morphogenetic Proteins, Hedgehogs, and Cbfa1

Yamaguchi, Akira; Komori, Toshihisa; Suda, Toshio

doi:10.1210/edrv.21.4.0403

Cited by 528 publications

(367 citation statements)

References 207 publications

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“…The induction of cbfa-1 gene expression observed is essential for osteoblast function and differentiation. It is also a critical gene involved in bone matrix deposition [56]. Early upregulation of collagen Ia1 confirmed its induction before any other current matrix component and prior to ALP [28,57,58].…”

Section: Discussionmentioning

confidence: 82%

Fetal bone cells for tissue engineering

Montjovent

Burri

Mark

et al. 2004

Bone

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We envision the use of human fetal bone cells for engineered regeneration of adult skeletal tissue. A description of their cellular function is then necessary. To our knowledge, there is no description of human primary fetal bone cells treated with differentiation factors. The characterization of fetal bone cells is particularly important as the pattern of secreted proteins from osteoblasts has been shown to change during aging. In the first part of this work, human primary fetal bone cells were compared to adult bone cells and mesenchymal stem cells for their ability to proliferate and to differentiate into osteoblasts in vitro. Cell proliferation, gene expression of bone markers, alkaline phosphatase (ALP) activity, and mineralization were analyzed during a time-course study. In the second part of this paper, bone fetal cells behavior exposed to osteogenic factors is further detailed. The doubling time of fetal bone cells was comparable to mesenchymal stem cells but significantly shorter than for adult bone cells. Gene expression of cbfa-1, ALP, a1 chain of type I collagen, and osteocalcin were upregulated in fetal bone cells after 12 days of treatment, with higher inductions than for adult and mesenchymal stem cells. The increase of ALP enzymatic activity was stronger for fetal than for adult bone cells reaching a maximum at day 10, but lower than for mesenchymal stem cells. Importantly, the mineralization process of bone fetal cells started earlier than adult bone and mesenchymal stem cells. Proliferation of fetal and adult bone cells was increased by dexamethasone, whereas 1a,25-dihydroxyvitamin D 3 did not show any proliferative effect. Mineralization studies clearly demonstrated the presence of calcium deposits in the extracellular matrix of fetal bone cells. Nodule formation and calcification were strongly increased by the differentiation treatment, especially by dexamethasone. This study shows for the first time that human primary fetal bone cells could be of great interest for bone research, due to their fast growth rate and their ability to differentiate into mature osteoblasts. They represent an interesting and promising potential for therapeutic use in bone tissue engineering.

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Section: Discussionmentioning

confidence: 82%

Fetal bone cells for tissue engineering

Montjovent

Burri

Mark

et al. 2004

Bone

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“…It is unclear how MSC seeding density relates to proliferative rate. Cell contact inhibition induces growth arrest in C3H10T1/2 cells at confluence, which is a murine fibroblast cell line with similar phenotypical characteristics to MSCs; 19 this growth arrest of C3H10T1/2 is reversed by reseeding the cells at lower density. 20 Hence, establishing MSC cultures at lower cell seeding densities may similarly reduce the effects of contact inhibition, maintaining a greater proportion of cells in cycle.…”

Section: Discussionmentioning

confidence: 99%

The cell culture expansion of bone marrow stromal cells from humans with spinal cord injury: implications for future cell transplantation therapy

et al. 2008

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Study design: Previous studies have shown that transplantation of bone marrow stromal cells (MSCs) in animal models of spinal cord injury (SCI) encourages functional recovery. Here, we have examined the growth in cell culture of MSCs isolated from individuals with SCI, compared with non-SCI donors. Setting: Centre for Spinal Studies, Midland Centre for Spinal Injuries, RJAH Orthopaedic Hospital, Oswestry, UK. Methods: Bone marrow was harvested from the iliac crest of donors with long-term SCI (43 months, n ¼ 9) or from non-SCI donors (n ¼ 7). Mononuclear cells were plated out into tissue culture flasks and the adherent MSC population subsequently expanded in monolayer culture. MSC were passaged by trypsinization at 70% confluence and routinely seeded into new flasks at a density of 5 Â 10 3 cells per cm 2 . Expanded cell cultures were phenotypically characterized by CD-immunoprofiling and by their differentiation potential along chondrocyte, osteoblast and adipocyte lineages. The influence of cellseeding density on the rate of cell culture expansion and degree of cell senescence was examined in separate experiments. Results: In SCI, but not in non-SCI donors the number of adherent cells harvested at passage I was age-related. The proliferation rate (culture doubling times) between passages I and II was significantly greater in cultures from SCI donors with cervical lesions than in those with thoracic lesions. There was no significant difference, however, in either the overall cell harvests at passages I or II or in the culture doubling times between SCI and non-SCI donors. At passage II, more than 95% of cells were CD34Àve, CD45Àve and CD105 þ ve, which is characteristic of human MSC cultures. Furthermore, passage II cells differentiated along all three mesenchymal lineages tested. Seeding passage I-III cells at cell densities lower than 5 Â 10 3 cells per cm 2 significantly reduced culture doubling times and significantly increased overall cell harvests while having no effect on cell senescence. Conclusion: MSCs from individuals with SCI can be successfully isolated and expanded in culture; this is encouraging for the future development of MSC transplantation therapies to treat SCI. Age, level of spinal injury and cell-seeding density were all found to relate to the growth kinetics of MSC cultures in vitro, albeit in a small sample group. Therefore, these factors should be considered if either the overall number or the timing of MSC transplantations post-injury is found to relate to functional recovery.

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“…As BMP-2 promotes osteoblast differentiation in human osteoblastic cells and osteosarcoma cells by inducing Runx2 expression and Runx2-dependent genes, 10,18 we also determined whether the proapoptotic effect of statins in …”

Section: Statin-induced Osteosarcoma Cell Apoptosis Occurs Independenmentioning

confidence: 99%

“…BMP-2, a member of the TGF beta superfamily, and Runx2, a master transcription factor acting as BMP effector, are important regulatory signals required for osteoblast differentiation. 10,11 Runx2 promotes the expression of phenotypic markers in postproliferative osteoblasts 11,12 and induces suppression of preosteoblastic cell proliferation, 13,14 which contributes to promote osteoblast maturation. Osteosarcoma cells are often characterized by loss of differentiated phenotype with decreased expression of osteoblast markers.…”

Section: Introductionmentioning

confidence: 99%

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

et al. 2006

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Osteosarcoma is the most common primary bone tumour in young adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of osteosarcoma treatment. The identification of signals that promote apoptosis may provide clues to develop new therapeutic strategies for chemoresistant osteosarcoma. Here, we show that lipophilic statins (atorvastatin, simvastatin, cerivastatin) markedly induce caspases-dependent apoptosis in various human osteosarcoma cells, independently of bone morphogenetic protein (BMP)-2 signaling and cell differentiation. Although statins increased BMP-2 expression, the proapoptotic effect of statins was not prevented by the BMP antagonist noggin, and was abolished by mevalonate and geranylgeranylpyrophosphate, suggesting the involvement of defective protein geranylgeranylation. Consistently, lipophilic statins induced membrane RhoA relocalization to the cytosol and inhibited RhoA activity, which resulted in decreased phospho-p42/p44-mitogen-activated protein kinases (MAPKs) and Bcl-2 levels. Constitutively active RhoA rescued phospho-p42/p44-MAPKs and Bcl-2 and abolished statininduced apoptosis. Thus, lipophilic statins induce caspasedependent osteosarcoma cell apoptosis by a RhoA-p42/p44 MAPKs-Bcl-2-mediated mechanism, independently of BMP-2 signaling and cell differentiation.

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Regulation of Osteoblast Differentiation Mediated by Bone Morphogenetic Proteins, Hedgehogs, and Cbfa1

Cited by 528 publications

References 207 publications

Fetal bone cells for tissue engineering

Fetal bone cells for tissue engineering

The cell culture expansion of bone marrow stromal cells from humans with spinal cord injury: implications for future cell transplantation therapy

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

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