Osteopontin—a molecule for all seasons

Mazzali, Marrilda; Kipari, Tiina; Ophascharoensuk, Vuddhidej; Wesson, Jeffrey A.; Johnson, Richard J.; Hughes, Jeremy

doi:10.1093/qjmed/95.1.3

Cited by 335 publications

(300 citation statements)

References 80 publications

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“…Although OPN is well known to have a role in macrophage infiltration, 40 and in vitro studies have demonstrated an enhanced chemotactic function of MMP-cleaved OPN, 32,41 no previous in vivo study has shown whether MMP-cleaved OPN is also chemotactic. Earlier studies demonstrated that the expression of OPN correlates well with macrophage infiltration in various experimental models of renal injury.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

127

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A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early-and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early-and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis. KEYWORDS: Epithelial-mesenchymal transition; macrophage; matrix metalloproteinase-9; osteopontin; renal fibrosis; tubular epithelial cell Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, belongs to a large family of zinc-dependent matrixdegrading enzymes called matrix metalloproteinases (MMPs) that have an important role in both physiological and pathological conditions in vivo. 1 MMPs are well known for their anti-fibrotic effect due to their ability to degrade and remodel extracellular matrix (ECM) proteins, however it has been recognized that MMPs can also exert pro-fibrotic effect under various pathological conditions.Myofibroblasts are the effector cells responsible for the production and secretion of ECM in renal fibrosis. It has been reported that myofibroblasts can derive from the activation of renal interstitial fibroblasts, perivascular fibroblasts and pericytes, from bone marrow-derived stem cells and

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

127

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“…Osteopontin is a multifunctional phosphorylated glycoprotein secreted by osteoblasts, and has been suggested to be present at an early stage of bone development and to promote the attachment of osteoblasts to the extracellular matrix [36]. Osteopontin is involved in bone remodelling [37] whilst osteocalcin is a marker of primary bone formation and is produced by osteoblasts [38]. While the precise role of osteocalcin is still under and OCN expression did not show statistical significant differences across the substrates, a trend of enhanced expression on LASER-modified surfaces was observed.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Skeletal stem cell and bone implant interactions are enhanced by LASER titanium modification

Sisti

Andrés

Johnston

et al. 2016

Biochemical and Biophysical Research Communications

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“…[4][5][6] Osteopontin (OPN) is a multifunctional bone matrix associated glycoprotein secreted by many cell types including lymphocytes, osteoclasts, endothelial cells and tumoral cells. 7 OPN expression by human cells is mainly regulated by the bone-specific transcription factor Runx2, namely also Cbfa1 (Runx2/Cbfa1), as demonstrated in bone cells, normal mammary cells and breast cancer cells. [8][9][10][11] Two different isoforms (Runx2/ Cbfa1/I and Runx2/Cbfa1/II) have been described in human osteoblastic cells, both able to regulate OPN expression.…”

Section: Introductionmentioning

confidence: 99%

Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients

et al. 2005

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Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138 þ cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.

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Osteopontin—a molecule for all seasons

Cited by 335 publications

References 80 publications

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Skeletal stem cell and bone implant interactions are enhanced by LASER titanium modification

Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients

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