CiteULike: heliopais bone_formation

Transcription factors controlling osteoblastogenesis

Pierre Marie — 2008-04-25T14:06:38-00:00

Archives of Biochemistry and Biophysics, Vol. In Press, Corrected Proof

The recent development of molecular biology and mouse genetics and the analysis of the skeletal phenotype induced by genetic mutations in humans led to a better understanding of the role of transcription factors that govern bone formation. This review summarizes the role of transcription factors in osteoblastogenesis and provides an integrated perspective on how the activities of multiple classes of factors are coordinated for the complex process of developing the osteoblast phenotype. The roles of Runx2, the principal transcriptional regulator of osteoblast differentiation, Osterix, [beta]-Catenin and ATF which act downstream of Runx2, and other transcription factors that contribute to the control of osteoblastogenesis including the AP1, C/EBPs, PPAR[gamma] and homeodomain, helix-loop-helix proteins are discussed. This review also updates the regulation of transcription factor expression by signaling factors and hormones that control osteoblastogenesis.

Gene profile analysis of osteoblast genes differentially regulated by histone deacetylase inhibitors

Tania Schroeder — 2007-10-16T08:21:18-00:00

BMC Genomics, Vol. 8 (09 October 2007), 362.

Microarray gene expression profiling of human osteoarthritic bone suggests altered bone remodelling, WNT and TGF beta/BMP signalling

Blair Hopwood — 2007-10-01T06:39:53-00:00

Arthritis Research & Therapy, Vol. 9 (27 September 2007), R100.

BMP1 controls TGFbeta1 activation via cleavage of latent TGFbeta-binding protein

Gaoxiang Ge — 2008-04-25T11:32:30-00:00

J. Cell Biol., Vol. 175, No. 1. (9 October 2006), pp. 111-120.

Transforming growth factor beta1 (TGFbeta1), an important regulator of cell behavior, is secreted as a large latent complex (LLC) in which it is bound to its cleaved prodomain (latency-associated peptide [LAP]) and, via LAP, to latent TGFbeta-binding proteins (LTBPs). The latter target LLCs to the extracellular matrix (ECM). Bone morphogenetic protein 1 (BMP1)-like metalloproteinases play key roles in ECM formation, by converting precursors into mature functional proteins, and in morphogenetic patterning, by cleaving the antagonist Chordin to activate BMP2/4. We provide in vitro and in vivo evidence that BMP1 cleaves LTBP1 at two specific sites, thus liberating LLC from ECM and resulting in consequent activation of TGFbeta1 via cleavage of LAP by non-BMP1-like proteinases. In mouse embryo fibroblasts, LAP cleavage is shown to be predominantly matrix metalloproteinase 2 dependent. TGFbeta1 is a potent inducer of ECM formation and of BMP1 expression. Thus, a role for BMP1-like proteinases in TGFbeta1 activation completes a novel fast-forward loop in vertebrate tissue remodeling. 10.1083/jcb.200606058

Genomic approaches to identifying transcriptional regulators of osteoblast differentiation

Joseph Stains — 2008-02-26T15:36:11-00:00

Genome Biology, Vol. 4, No. 7. (1 July 2003), 222.

Recent microarray studies of mouse and human osteoblast differentiation in vitro have identified novel transcription factors that may be important in the establishment and maintenance of differentiation. These findings help unravel the pattern of gene-expression changes that underly the complex process of bone formation.

Transcriptome analysis of fetal metatarsal long bones by microarray, as a model for endochondral bone formation

Rachael Sugars — 2008-02-26T15:11:03-00:00

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1763, No. 10. (October 2006), pp. 1031-1039.

Endochondral bone formation is orchestrated by mesenchymal cell condensation to form cartilage anlagen, which act as a template for bone formation and eventual mineralization. The current study performed gene expression analysis to examine pre- and post-mineralization stages (E15 and E19) of endochondral bone formation, using fetal metatarsal long bones as a model. An extensive number of genes were differentially expressed, with 543 transcripts found to have at least 2-fold up-regulation and 742 with a greater than 2-fold down-regulation. A bioinformatics approach was adopted based on gene ontology groups, and this identified genes associated with the regulation of signaling and skeletal development, cartilage replacement by bone, and matrix degradation and turnover. Transcripts linked to skeletal patterning, including Hoxd genes 10-12, Gli2 and Noggin were considerably down-regulated at E19. Whereas genes associated with bone matrix formation and turnover, ACP5, MMP-13, bone sialoprotein, osteopontin, dentin matrix protein-1 and MMP-9 all were distinctly up-regulated at this later time point. This approach to studying the formation of the primary ossification center provides a unique picture of the developmental dynamics involved in the molecular and biochemical processes during this intricately regulated process.

A gene expression profile for endochondral bone formation: oligonucleotide microarrays establish novel connections between known genes and BMP-2-induced bone formation in mouse quadriceps

Brian Clancy — 2008-02-26T15:06:43-00:00

Bone, Vol. 33, No. 1. (July 2003), pp. 46-63.

Endochondral bone formation has been fairly well characterized from a morphological perspective and yet this process remains largely undefined at molecular and biochemical levels. In vitro and in vivo studies have shown that human bone morphogenetic protein-2 (hBMP-2) is an important developmental growth and differentiation factor, capable of inducing ectopic bone formation in vivo. This study evaluated several aspects of the osteogenic effect of hBMP-2 protein injected into quadriceps of female C57B1/6J SCID mice. Mice were euthanized 1, 2, 3, 4, 7, and 14 days postinjection and muscles were collected for several methods of analysis. Hematoxylin and eosin-stained sections of muscles injected with formulation buffer showed no evidence of osteogenesis. In contrast, sections of muscles injected with hBMP-2 showed evidence of endochondral bone formation that progressed to mineralized bone by day 14. In addition, radiographs of mice injected with hBMP-2 showed that much of the quadriceps muscle had undergone mineralization by day 14. Labeled mRNA solutions were prepared and hybridized to oligonucleotide arrays designed to monitor ~1300 murine, full-length genes. Changes in gene expression associated with hBMP-2 were determined from time-matched comparisons between buffer and hBMP-2 samples. A gene expression profile was created for 215 genes that showed greater than 4-fold changes at one or more of the indicated time points. One hundred twenty-two of these genes have previously been associated with bone or cartilage metabolism and showed significant increases in expression, e.g., aggrecan (Agc1), runt related transcription factor 2 (Runx2), bone Gla protein 1 (Bglap1), and procollagens type II (Col2a1) and X (Col10a1). In addition, there were 93 genes that have not been explicitly associated with bone or cartilage metabolism. Two of these genes, cytokine receptor-like factor-1 (Crlf1) and matrix metalloproteinase 23 (Mmp23), showed peak changes in gene expression of 15- and 40-fold on days 4 and 7, respectively. In situ hybridizations of muscle sections showed that Mmp23 and Crlf1 mRNAs were expressed in chondrocytes and osteoblasts, suggesting a role for both proteins in some aspect of cartilage or bone formation. In conclusion, oligonucleotide arrays enabled a broader view of endochondral bone formation than has been reported to date. An increased understanding of the roles played by these gene products will improve our understanding of skeletogenesis, fracture repair, and pathological conditions such as osteoporosis.

Discovery of osteoblast-associated genes using cDNA microarrays

A Raouf — 2008-02-26T15:00:59-00:00

Bone, Vol. 30, No. 3. (March 2002), pp. 463-471.

Osteoblast maturation is a complex process and involves distinct genotypic changes that are accompanied by specific phenotypic alterations. To identify new bone-related genes in osteoblasts we utilized the high-density mouse GEM1 microarray gene chip from IncyteGenomics, Inc. (St. Louis, Mo). We examined the expression profiles of over 8700 genes during the proliferation (day 3) and the mineralization (day 34) phases of MC3T3-E1 development. More than 8600 genes provided measurable signals. Of these genes, 252 were found to be differentially expressed on days 3 and 34. A large number of these genes have never been previously recognized in the context of osteoblast development. Approximately, 60% of the genes with expressions that were dominant in proliferating osteoblasts consisted of growth-related genes such as TACC3 and Pr22. The expressions of TIS21/BTG2, and a novel gene EST350, were found to peak during the differentiation phase (day 12), suggesting that they may play important roles in osteoblast differentiation. The majority of the genes with expressions that were dominant during the mineralization phase consisted of signal transduction genes and extracellular matrix (ECM) proteins such as lumican and cystatin-C. It is significant that lumican expression could not be detected on day 3, which indicates that this gene may serve as an important marker of postmitotic osteoblasts. The establishment of the expression profiles of these and other genes with various phases of MC3T3-E1 osteoblast development will allow us to distinguish the molecular events at different phases of osteoblast biology.

Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells

Huilin Qi — 2008-02-26T14:51:24-00:00

Proceedings of the National Academy of Sciences, Vol. 100, No. 6. (18 March 2003), pp. 3305-3310.

Single human bone marrow-derived mesodermal progenitor cells (MPCs) differentiate into osteoblasts, chondrocytes, adipocytes, myocytes, and endothelial cells. To identify genes involved in the commitment of MPCs to osteoblasts we examined the expressed gene profile of undifferentiated MPCs and MPCs induced to the osteoblast lineage for 1-7 days by cDNA microarray analysis. As expected, growth factor, hormone, and signaling pathway genes known to be involved in osteogenesis were activated during differentiation. In addition, 41 transcription factors (TFs) were differentially expressed over time, including TFs with known roles in osteoblast differentiation and TFs not known to be involved in osteoblast differentiation. As the latter group of TFs coclustered with osteogenesis-specific TFs, they may play a role in osteoblast differentiation. When we compared the gene expression profile of MPCs induced to differentiate to chondroblasts and osteoblasts, significant differences in the nature and/or timing of gene activation were seen. These studies indicate that in vitro differentiation cultures in which MPCs are induced to one of multiple cell fates should be very useful for defining signals important for lineage-specific differentiation. 10.1073/pnas.0532693100