Differentiation of Human Marrow Stromal Precursor Cells: Bone Morphogenetic Protein-2 Increases OSF2/CBFA1, Enhances Osteoblast Commitment, and Inhibits Late Adipocyte Maturation

Gori, Francesca; Thomas, Thierry; Hicok, Kevin C.; Spelsberg, Thomas C.; Riggs, B. Lawrence

doi:10.1359/jbmr.1999.14.9.1522

Cited by 278 publications

(242 citation statements)

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“…An alternative explanation involves the developmental link between adipogenesis, chondrogenesis, and osteogenesis. These cells share a common mesenchymal cell precursor that can be induced to differentiate into one of these cell types in vitro by adjustment of the culture microenvironment (46,47). It is thus possible that an early event in the initiation and progression of OA is a preferential shift toward osteoblastogenesis resulting from the downregulation of PPAR signaling.…”

Section: Discussionmentioning

confidence: 99%

Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/ORT mouse

Watters¹,

Cheng²,

Pickarski³

et al. 2007

Arthritis & Rheumatism

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Objective. The biologic changes associated with osteoarthritis (OA) are incompletely understood. The aim of this study was to elucidate the molecular mechanisms underlying OA progression in an STR/Ort murine model of spontaneous disease.Methods. Global patterns of gene expression were assessed using microarray analysis of articular cartilage/subchondral bone from the tibial plateaus of STR/Ort mice at 3, 9, and 12 months of age. The age-dependent severity of osteophyte formation and extent of cartilage damage were determined in the corresponding femurs using microfocal computed tomography and the Mankin histologic scoring system. Pathway analysis was used to identify the functions of genes associated with OA progression, and changes in gene expression were confirmed using immunohistochemistry.Results. Six hundred twenty-one genes were associated with both osteophyte formation and cartilage damage in the STR/Ort joints. Genes involved in the development/function of connective tissue and in lipid metabolism were most significantly enriched and regulated during disease progression. Genes directly interacting with peroxisome proliferator-activated receptor ␣ (PPAR␣)/PPAR␥ were down-regulated, whereas those genes involved with connective tissue remodeling were up-regulated during disease progression. Associations of down-regulation of myotubularinrelated phosphatase 1 (a phosphoinositide 3-phosphatase involved in lipid signaling) and up-regulation of biglycan (a member of the small leucine-rich protein family known to modulate osteoblast differentiation and matrix mineralization) with OA progression were confirmed by immunohistochemistry.Conclusion. Since adipogenesis and osteogenesis are inversely related in the developing skeletal tissue, these results suggest that a shift in the differentiation of mesenchymal cells from adipogenesis toward osteogenesis is a component of the OA pathophysiologic processes occurring in the tibial plateau joints of STR/Ort mice.

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Section: Discussionmentioning

confidence: 99%

Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/ORT mouse

Watters¹,

Cheng²,

Pickarski³

et al. 2007

Arthritis & Rheumatism

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“…The formation of mineralized matrix nodules was determined by alizarin red-S staining (25). In parallel experiments, calcium accumulation in the matrix was quantitated by solubilizing the deposited calcium with 0.6 N HCl overnight at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Cloning and Characterization of a Novel Protein Kinase That Impairs Osteoblast Differentiation in Vitro

Kearns

Donohue

Sanyal

et al. 2001

Journal of Biological Chemistry

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The bone morphogenic proteins (BMPs) play a key role in skeletal development and patterning. Using the technique of differential display polymerase chain reaction (ddPCR), we have identified a novel gene whose expression is increased during BMP-2-induced differentiation of the prechondroblastic cell line, MLB13MYC clone 17, to an osteoblastic phenotype. The 6.5-kilobase mRNA recognized by this ddPCR product is increased 10-fold by BMP-2 treatment of the MLB13MYC clone 17 cells. The mRNA recognized by this ddPCR product is also increased as MC3T3-E1 cells recapitulate the program of osteoblast differentiation during prolonged culture. The full-length transcript corresponding to this ddPCR product was cloned from a MLB13MYC clone 17 cell cDNA library. Analysis of the deduced amino acid sequence demonstrated that this gene encodes a novel 126-kDa putative serine/threonine protein kinase containing a nuclear localization signal. The kinase domain, expressed in Escherichia coli, is capable of autophosphorylation as well as phosphorylation of myelin basic protein. The gene was, therefore, named BIKe (BMP-2-Inducible Kinase). The BIKe nuclear localization signal is able to direct green fluorescent protein to the nucleus in transfected COS-7 cells. When stably expressed in MC3T3-E1 cells, BIKe significantly decreases alkaline phosphatase activity and osteocalcin mRNA levels and retards mineral deposition relative to vector control. This novel kinase, therefore, is likely to play an important regulatory role in attenuating the program of osteoblast differentiation.Numerous investigations have been directed at elucidating factors that regulate osteoblast differentiation (1). The bone morphogenetic proteins (BMPs) 1 are potent local factors that promote osteoblast differentiation during development as well as during bone remodeling (2). The molecular events downstream of BMP signaling that result in tissue-specific gene expression and skeletal development have only been partially elucidated. The binding of BMPs to their receptors leads to the assembly of a receptor complex in which the type II receptor phosphorylates and activates the type I receptor. As a result, pathway-restricted SMADs are phosphorylated, leading to interactions with the common mediator SMAD, smad4 (3). This complex is then translocated to the nucleus, where it modulates transcription of target genes. BMP signaling can also interfere with the effects of other growth and differentiation factors. It has been demonstrated that BMP-2 treatment of mesangial cells prevents phosphorylation of a transcription factor, Elk1, in response to platelet-derived growth factor (PDGF) signaling. This effectively inhibits PDGF-induced Elk-1-mediated transcription, and blocks PDGF-induced transcription of c-fos, an Elk-1 target (4). BMP-7 has been shown to be a potent inducer of Cbfa1, a transcription factor belonging to the runt-domain gene family that, in turn, regulates the expression of several genes in the osteoblast (5). Although Cbfa1 expression is necessary, it a...

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“…Patients on glucocorticoid therapy not only lose bone but also accumulate large amounts of marrow fat (fatty marrow), indicating that glucocorticoid has altered lineage commitment of MSC to adipocytes at the expense of osteoblasts because these two pathways have a reciprocal relationship [61][62][63][64]. Thus, one possible mechanism by which glucocorticoids alter MSC fate determination is through the induction of the master adipogenic regulator peroxisome proliferator-activated receptor gamma (PPAR) [65;66], which is transcriptionally activated by the CCAAT/enhancer binding protein (C/EBP) family transcription factors in response to glucocorticoid [67][68][69][70] (Figure 2).…”

Section: Glucocorticoid Effects On Bone Marrow Mesenchymal Stem Cellsmentioning

confidence: 99%

Mechanism of Glucocorticoid-Induced Osteoporosis: An Update

Shi¹,

Chutkan²,

Hamrick³

et al. 2012

Glucocorticoids - New Recognition of Our Familiar Friend

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Differentiation of Human Marrow Stromal Precursor Cells: Bone Morphogenetic Protein-2 Increases OSF2/CBFA1, Enhances Osteoblast Commitment, and Inhibits Late Adipocyte Maturation

Cited by 278 publications

References 85 publications

Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/ORT mouse

Inverse relationship between matrix remodeling and lipid metabolism during osteoarthritis progression in the STR/ORT mouse

Cloning and Characterization of a Novel Protein Kinase That Impairs Osteoblast Differentiation in Vitro

Mechanism of Glucocorticoid-Induced Osteoporosis: An Update

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