Osteopontin expression and function: Role in bone remodeling

Denhardt, David T.; Noda, Masaki

doi:10.1002/(sici)1097-4644(1998)72:30/31+<92::aid-jcb13>3.0.co;2-a

Cited by 392 publications

(252 citation statements)

References 51 publications

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“…Fresh medium containing the individual compounds was supplemented three times during the 8-to 10-day culture period. Cells were then fixed and stained for TRAP activity as described (10) (20,21) that may in part account for the improved bone strength and reduced fracture rate found in 1,25(OH) 2 D 3 or 1␣-hydroxyvitamin D 3 -treated osteoporotic patients (20,23). Our results suggest that 2MD exhibits at very low concentrations a marked and unexpected activity in stimulating the synthesis of new bone.…”

Section: Discussionmentioning

confidence: 65%

A potent analog of 1α,25-dihydroxyvitamin D ₃ selectively induces bone formation

Shevde

Plum

Clagett‐Dame

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

171

160

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1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] is a principal regulator of calcium and phosphorus homeostasis through actions on intestine, kidney, and bone. 1,25(OH) 2D3 is not considered to play a significant role in bone formation, except for its role in supporting mineralization. We report here on the properties of 2-methylene-19-nor-(20S)-1␣,25(OH) 2D3 (2MD), a highly potent analog of 1,25(OH)2D3 that induces bone formation both in vitro and in vivo. Selectivity for bone was first demonstrated through the observation that 2MD is at least 30-fold more effective than 1,25(OH) 2D3 in stimulating osteoblast-mediated bone calcium mobilization while being only slightly more potent in supporting intestinal calcium transport. 2MD is also highly potent in promoting osteoblast-mediated osteoclast formation in vitro, a process essential to both bone resorption and formation. Most significantly, 2MD at concentrations as low as 10 ؊12 M causes primary cultures of osteoblasts to produce bone in vitro. This effect is not found with 1,25(OH) 2D3 even at 10 ؊8 M, suggesting that 2MD might be osteogenic in vivo. Indeed, 2MD (7 pmol͞day) causes a substantial increase (9%) in total body bone mass in ovariectomized rats over a 23-week period. 1,25(OH) 2D3 (500 pmol three times a week) only prevented the bone loss associated with ovariectomy and did not increase bone mass. These results indicate that 2MD is a potent bone-selective analog of 1,25(OH) 2D3 potentially effective in treating bone loss diseases.V itamin D-deficiency diseases such as rickets and osteomalacia represent a failure in bone formation primarily caused by a failure of mineralization (1-3). Indeed, early investigations into the underlying defect associated with rickets revealed that incubation of bone slices in media containing physiologic levels of calcium and phosphorus resulted in normal mineralization of rachitic matrix (3). Underwood and DeLuca (4) subsequently demonstrated that the mineralization defect associated with vitamin D deficiency is due directly to insufficient calcium and phosphorus in plasma at sites of mineralization. These early conclusions have been supported independently by recent studies that show that skeletal disease, which arises from deletion of the vitamin D receptor (VDR), the exclusive transcriptional mediator of vitamin D action in vivo, can be normalized in mice through lactose-containing diets high in calcium and phosphorus (5). Thus, there is little evidence that vitamin D plays a direct role in new bone formation apart from its action to maintain calcium and phosphorus levels in the blood.We recently discovered a class of vitamin D compounds modified at the 2-carbon position of the A ring that is highly potent. The introduction of a methylene group at carbon 2, removal of a methylene group at carbon 10, and alteration of the stereochemistry of the 20-carbon to yield the 20S-derivative resulted in 2-methylene-19-nor-(20S)-1␣,25(OH) 2 D 3 (2MD), a compound that exhibits an affinity for the VDR equal to that of 1,25-dihydroxyvitamin D...

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Section: Discussionmentioning

confidence: 65%

A potent analog of 1α,25-dihydroxyvitamin D ₃ selectively induces bone formation

Shevde

Plum

Clagett‐Dame

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

171

160

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“…Its expression is elevated in response to mechanical stress in bone and the vasculature (12,25,31). OPN levels are also elevated in response to the oxidative stresses existing in tumors, after reperfusion injury, and in inf lammatory diseases such as inf lammatory bowl disease, chronic obstructive pulmonary disease, and Parkinson's disease (17,32,33).…”

Section: Discussionmentioning

confidence: 99%

Osteopontin regulates hindlimb-unloading-induced lymphoid organ atrophy and weight loss by modulating corticosteroid production

Wang¹,

Shi²,

Denhardt

2007

Proc. Natl. Acad. Sci. U.S.A.

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Osteopontin (OPN), a multifunctional secreted phosphoglycoprotein, plays diverse roles in bone biology, immune regulation, cell survival, inflammation, and cancer metastasis. Here we show its role in determining lymphocyte homeostasis and body mass in response to hindlimb unloading (HU), a model for evaluating effects of weightlessness on the musculoskeletal and other physiological systems. Using this stress model, we compared OPN ؊/؊ mice with OPN ؉/؉ mice subjected to HU for 3 days. Whereas OPN ؉/؉ mice suffered a marked reduction of body weight and significant spleen and thymus atrophy, OPN ؊/؊ mice exhibited minor weight loss and much less spleen and thymus atrophy. The HU-induced lymphoid organ atrophy was the result of dramatically diminished numbers, respectively, of T and B cells in the spleen and CD4 ؉ CD8 ؉ double-positive cells in the thymus of OPN ؉/؉ mice. Increased levels of corticosterone, which modulates lymphocyte activation responses and apoptosis during stress, were found only in OPN ؉/؉ mice. Apoptotic cell death was evident in the spleen and thymus of OPN ؉/؉ mice subjected to HU but not in OPN ؊/؊ mice. Importantly, lymphocytes from both OPN ؉/؉ and OPN ؊/؊ mice were equally sensitive to corticosteroid-induced apoptosis. These results reveal that OPN is required for enhanced corticosterone production, immune organ atrophy, and weight loss in mice subjected to HU. apoptosis ͉ immune ͉ stress ͉ lymphocytes ͉ space flight

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“…OPN, an extracellular matrix protein secreted by a wide variety of cancers, functionally enables tumor progression (3)(4)(5)(6)(7)(8). The secreted phosphoprotein binds the ␣ v ␤ integrin and CD44 families of receptors to propagate cellular signals (8 -14).…”

mentioning

confidence: 99%

Ets-1 and Runx2 Regulate Transcription of a Metastatic Gene, Osteopontin, in Murine Colorectal Cancer Cells

Wai

Gao

et al. 2006

Journal of Biological Chemistry

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Osteopontin (OPN) is a sialic acid-rich phosphoprotein secreted by a wide variety of cancers. We have shown previously that OPN is necessary for mediating hepatic metastasis in CT26 colorectal cancer cells. Although a variety of stimuli can induce OPN, the molecular mechanisms that regulate OPN gene transcription in colorectal cancer are unknown. We hypothesized that cis-and trans-regulatory elements determine OPN transcription in CT26 cells. OPN transcription was analyzed in CT26 cancer cells and compared with YAMC (young adult mouse colon) epithelial cells. Clonal deletion analysis of OPN promoter-luciferase constructs identified cis-regulatory regions. A specific promoter region, nucleotide (nt) ؊107 to ؊174, demonstrated a >8.0-fold increase in luciferase activity in CT26 compared with YAMC. Gel-shift assays sublocalized two cis-regulatory regions, nt ؊101 to ؊123 and nt ؊121 to ؊145, which specifically bind CT26 nuclear proteins. Competition with unlabeled mutant oligonucleotides revealed that the regions nt ؊115 to ؊118 and nt ؊129 to ؊134 were essential for protein binding. Subsequent supershift and chromatin immunoprecipitation assays confirmed the corresponding nuclear proteins to be Ets-1 and Runx2. Functional relevance was demonstrated through mutations in the Ets-1 and Runx2 consensus binding sites resulting in >60% decrease in OPN transcription. Ets-1 and Runx2 protein expression in CT26 was ablated using antisense oligonucleotides and resulted in a >7-fold decrease in OPN protein expression. Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.Colorectal cancer continues to be the second leading cause of cancer-related deaths in the United States (1, 2). Many patients with advanced or recurrent disease develop distant metastases and fail locoregional therapy. The molecular mechanisms underlying tumor metastasis are not completely understood, but recent evidence implicates osteopontin (OPN) 2 as a key regulator of cancer cell metastasis.OPN, an extracellular matrix protein secreted by a wide variety of cancers, functionally enables tumor progression (3-8).The secreted phosphoprotein binds the ␣ v ␤ integrin and CD44 families of receptors to propagate cellular signals (8 -14). In colorectal cancer, gene profiling studies have identified a positive correlation between advanced or metastatic colon tumors and abundant OPN expression (15, 16). We have previously shown that stable, RNAi-mediated down-regulation of OPN expression in CT26 colon adenocarcinoma cells results in suppression of matrix metalloproteinase-2 (MMP-2) expression, decreased in vitro tumor cell motility and invasiveness, and attenuation of functional in vivo hepatic metastasis (17). Together, these data suggest that OPN is necessary for CT26 colorectal metastasis. Subsequent studies in our laboratory have confirmed that OPN protein expression is highly up-regulated in meta...

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Osteopontin expression and function: Role in bone remodeling

Cited by 392 publications

References 51 publications

A potent analog of 1α,25-dihydroxyvitamin D ₃ selectively induces bone formation

A potent analog of 1α,25-dihydroxyvitamin D ₃ selectively induces bone formation

Osteopontin regulates hindlimb-unloading-induced lymphoid organ atrophy and weight loss by modulating corticosteroid production

Ets-1 and Runx2 Regulate Transcription of a Metastatic Gene, Osteopontin, in Murine Colorectal Cancer Cells

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Osteopontin expression and function: Role in bone remodeling

Cited by 392 publications

References 51 publications

A potent analog of 1α,25-dihydroxyvitamin D 3 selectively induces bone formation

A potent analog of 1α,25-dihydroxyvitamin D 3 selectively induces bone formation

Osteopontin regulates hindlimb-unloading-induced lymphoid organ atrophy and weight loss by modulating corticosteroid production

Ets-1 and Runx2 Regulate Transcription of a Metastatic Gene, Osteopontin, in Murine Colorectal Cancer Cells

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A potent analog of 1α,25-dihydroxyvitamin D ₃ selectively induces bone formation

A potent analog of 1α,25-dihydroxyvitamin D ₃ selectively induces bone formation