Role of Cbfa1/Runx2 in the fluid shear stress induction of COX-2 in osteoblasts

Mehrotra, Meenal; Saegusa, Masatomo; Voznesensky, Olga; Pilbeam, Carol C.

doi:10.1016/j.bbrc.2006.01.084

Cited by 19 publications

(12 citation statements)

References 31 publications

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“…In addition, we found that FAK activity is also important for the OFF induction of PGE 2 . Whereas other studies have shown that expression of c-fos, (36)(37)(38)41,58) COX-2, (7,8,33,35,37,48,59) and OPN (34,47) is regulated by shear stress, this study is the first to show a relationship between FAK activity and the regulation of expression of these proteins. FAK 2/2 osteoblasts did exhibit a small but significant increase in c-fos and COX-2 expression and ERK activation after exposure to OFF, suggesting that these cells were able to detect and respond to FSS, albeit at a lesser degree than their control counterparts.…”

contrasting

confidence: 63%

“…In addition, we found that FAK activity is also important for the OFF induction of PGE 2 . Whereas other studies have shown that expression of c‐ fos ,

^{((^{36–38}))}

^{((^{41}))}

^{((^{58}))}

COX‐2,

^{((^{7}))}

^{((^{8}))}

^{((^{33}))}

^{((^{35}))}

^{((^{37}))}

^{((^{48}))}

^{((^{59}))}

and OPN

^{((^{34}))}

^{((^{47}))}

is regulated by shear stress, this study is the first to show a relationship between FAK activity and the regulation of expression of these proteins.…”

Section: Discussioncontrasting

confidence: 43%

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Focal Adhesion Kinase Is Important for Fluid Shear Stress-Induced Mechanotransduction in Osteoblasts

Young

Gerard-O’Riley

Kim³

et al. 2009

Journal of Bone and Mineral Research

121

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Mechanical loading of bone is important for maintenance of bone mass and structural stability of the skeleton. When bone is mechanically loaded, movement of fluid within the spaces surrounding bone cells generates fluid shear stress (FSS) that stimulates osteoblasts, resulting in enhanced anabolic activity. The mechanisms by which osteoblasts convert the external stimulation of FSS into biochemical changes, a process known as mechanotransduction, remain poorly understood. Focal adhesions are prime candidates for transducing external stimuli. Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase found in focal adhesions, may play a key role in mechanotransduction, although its function has not been directly examined in osteoblasts. We examined the role of FAK in osteoblast mechanotransduction using short interfering RNA (siRNA), overexpression of a dominant negative FAK, and FAK 2/2 osteoblasts to disrupt FAK function in calvarial osteoblasts. Osteoblasts were subjected to varying periods oscillatory fluid flow (OFF) from 5 min to 4 h, and several physiologically important readouts of mechanotransduction were analyzed including: extracellular signal-related kinase 1/2 phosphorylation, upregulation of c-fos, cyclooxygenase-2, and osteopontin, and release of prostaglandin E 2 . Osteoblasts with disrupted FAK signaling exhibited severely impaired mechanical responses in all endpoints examined. These data indicate the importance of FAK for both short and long periods of FSS-induced mechanotransduction in osteoblasts.

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contrasting

confidence: 63%

“…In addition, we found that FAK activity is also important for the OFF induction of PGE 2 . Whereas other studies have shown that expression of c‐ fos ,

^{((^{36–38}))}

^{((^{41}))}

^{((^{58}))}

COX‐2,

^{((^{7}))}

^{((^{8}))}

^{((^{33}))}

^{((^{35}))}

^{((^{37}))}

^{((^{48}))}

^{((^{59}))}

and OPN

^{((^{34}))}

^{((^{47}))}

is regulated by shear stress, this study is the first to show a relationship between FAK activity and the regulation of expression of these proteins.…”

Section: Discussioncontrasting

confidence: 43%

Focal Adhesion Kinase Is Important for Fluid Shear Stress-Induced Mechanotransduction in Osteoblasts

Young

Gerard-O’Riley

Kim³

et al. 2009

Journal of Bone and Mineral Research

121

View full text Add to dashboard Cite

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“…The previously-reported Runx2 consensus binding probe (Pcon) was used as a positive control 19 . As with the results of ChIP assay, binding complexes were detected predominantly with the P3 probe, and with other probes to a much lesser extent.…”

Section: Resultsmentioning

confidence: 99%

Runx2-Upregulated Receptor Activator of Nuclear Factor κB Ligand in Calcifying Smooth Muscle Cells Promotes Migration and Osteoclastic Differentiation of Macrophages

Byon

Sun

Chen

et al. 2011

ATVB

150

160

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Objective Clinical and experimental studies demonstrate the important roles of vascular smooth muscle cells (VSMC) in the pathogenesis of atherosclerosis. We have previously determined that osteogenic transcription factor, Runx2, is essential for VSMC calcification. The present studies characterized Runx2-regulated signals and their potential roles in vascular calcification. Methods and Results In vivo studies with atherogenic ApoE−/− mice demonstrated that increased oxidative stress was associated with upregualtion of Runx2 and receptor activator of nuclear factor κB ligand (RANKL), which colocalized in the calcified atherosclerotic lesions and were juxtaposed to infiltrated macrophages and osteoclast-like cells that are positively stained for an osteoclast marker, tartrate-resistant acid phosphatase (TRAP). Mechanistic studies using RNA interfering, a luciferase reporter system, chromatin immunoprecipitation and electrophoretic mobility shift assays identified that Runx2 regulated the expression of RANKL via a direct binding to the 5'-flanking region of the RANKL. Functional characterization revealed that RANKL did not induce VSMC calcification, nor RANKL was required for oxidative stress-induced VSMC calcification. Using a co-culture system, we demonstrated VSMC-expressed RANKL induced migration as well as differentiation of bone marrow-derived macrophages into multinucleated, TRAP-positive osteoclast-like cells. These effects were inhibited by the RANKL antagonist, osteoprotegerin, and with VSMC deficient in Runx2 or RANKL. Conclusions We demonstrate that Runx2 directly binds to the promoter and controls the expression of RANKL, which mediates the crosstalk between calcifying VSMC and migration and differentiation of macrophages into osteoclast-like cells in the atherosclerotic lesions. Our studies provide novel mechanistic insights into the regulation and function of VSMC-derived RANKL in the pathogenesis of atherosclerosis and vascular calcification.

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“…It has recently been shown that the promoter of the COX2 gene has a Runx2‐binding site and is regulated by Runx2 transcriptional activity.

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To determine whether BBR increases COX2 expression by Runx2, we conducted a luciferase reporter assay using the COX2 promoter in the absence or presence of Runx2 or BBR in HEK293 cells. Similar to a previous report,

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Runx2 stimulated COX2 promoter activity and BBR additionally enhanced Runx2 transcriptional activity at the COX2 promoter (Fig. 5D), implying that COX2 is the target gene of Runx2 and its expression is regulated by BBR.…”

Section: Resultsmentioning

confidence: 99%

Berberine Promotes Osteoblast Differentiation by Runx2 Activation With p38 MAPK

Lee

Suh

hyunnam

et al. 2008

Journal of Bone and Mineral Research

108

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Berberine (BBR) has been implicated in bone biology. Although BBR reduces osteoporosis by enhancing BMD and inhibiting osteoclast activity, the effects of BBR on osteoblasts during the process of osteogenesis have not been thoroughly studied. In osteoblastic cells, BBR enhanced the expression of osteogenic marker genes including osteopontin and osteocalcin and promoted the transcriptional activity of the key osteogenic transcription factor Runx2. In osteoblasts, BBR increased the binding of Runx2 to the promoter region of osteopontin. The recruitment of co-factors such as p300 and HDAC1 to the promoter regions of osteopontin and osteocalcin was regulated by BBR, resulting in an enhancement in the expression of those genes. Furthermore, BBR activated p38 mitogen-activated protein kinase (MAPK) and increased cyclooxygenase 2 (COX2) expression, which are key factors in osteoblast differentiation. Consistently, a p38 MAPKspecific inhibitor attenuated the effect of BBR on osteogenesis, whereas p38 MAPK overexpression augmented BBR-induced osteogenic gene expression. Moreover, BBR stimulated bone area formation in calvarial organ culture. Taken together, these findings indicate that BBR promotes osteoblast differentiation through activation of Runx2 by p38 MAPK. Therefore, BBR may be a potential therapeutic agent to treat bone-related disorders including osteoporosis.

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Role of Cbfa1/Runx2 in the fluid shear stress induction of COX-2 in osteoblasts

Cited by 19 publications

References 31 publications

Focal Adhesion Kinase Is Important for Fluid Shear Stress-Induced Mechanotransduction in Osteoblasts

Focal Adhesion Kinase Is Important for Fluid Shear Stress-Induced Mechanotransduction in Osteoblasts

Runx2-Upregulated Receptor Activator of Nuclear Factor κB Ligand in Calcifying Smooth Muscle Cells Promotes Migration and Osteoclastic Differentiation of Macrophages

Berberine Promotes Osteoblast Differentiation by Runx2 Activation With p38 MAPK

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