Susan R Rittling

Harvard University, Cambridge, Massachusetts, United States

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Publications (122)619.4 Total impact

  • S R Rittling · R Singh
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    ABSTRACT: Since its initial identification as one of the genes most highly upregulated upon T-cell activation, osteopontin (or Eta-1, as it was designated then) has been demonstrated to have many roles in the regulation of the immune response on multiple levels. It contributes to the development of immune-mediated and inflammatory diseases, and it regulates the host response to infection. In some cases, the mechanisms of these effects have been elucidated, while other mechanistic functions of the protein remain obscure. The protein itself makes these analyses complex, since it binds to a series of different integrins, and in addition to its classically secreted form, an intracellular form of osteopontin has been identified, which participates in several aspects of immune regulation. In this review, we focus on the role of osteopontin in a series of immune-related diseases, particularly those where significant advances have been made in recent years: multiple sclerosis, rheumatoid arthritis, lupus and related diseases, Sjögren's disease, colitis, and 1 area of inflammatory pathology, alcoholic and nonalcoholic liver diseases. A recurring theme in these diseases is a link between osteopontin and pathogenic T cells, particularly T helper 17 cells, where osteopontin produced by dendritic cells supports IL-17 expression, contributing to pathology. In addition, a role for osteopontin in B-cell differentiation is becoming clear. In general, osteopontin contributes to pathology in these diseases, but there are examples where it has a protective role; deciphering the mechanisms underlying these differences and the specific receptors for osteopontin will be a research challenge for the future. Aside from its newly discovered role in the development of Sjögren's disease, the role of osteopontin in inflammatory conditions in the oral cavity is still poorly understood. Elucidation of this role will be of interest. © International & American Associations for Dental Research 2015.
    No preview · Article · Sep 2015 · Journal of dental research
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    ABSTRACT: Using the subcutaneous chamber model of infection, we showed previously that a mixture of four endodontic pathogens (EP: P. intermedia, F. nucleatum, S. intermedius and P. micra) are able to persist without clearance for up to seven days, while a non-pathogenic oral species, S. mitis, was substantially cleared in this time. Here we have compared the cytokine response inside the chambers against these microorganisms. A majority of cytokines tested (17/24) showed different patterns of expression. Several cytokines had a peak of expression at 2 h after infection in response to the EP, while none showed this pattern in S. mitis infections. Chemokines were uniformly present at similar or higher levels in response to S. mitis, with redundant expression of CXCR2 ligands, while several growth/survival factors were present at higher levels in EP infections. Protease activity expressed by EP may be responsible for the lower levels of some chemokines. T-cell associated cytokines were in general expressed at extremely low levels, and did not differ between the two infections. The inflammatory markers IL-6, IL-1α and IL1-β were expressed at similar levels in both infections at early times, while TNFα was preferentially present in S. mitis infections. In EP infected chambers, reciprocal changes in levels of IL-6 and IL-1α were observed at later times suggesting a switch in the inflammatory response. Analysis of the cytokine response to infection with the individual species from the EP mix suggests that P. intermedia drives this inflammatory switch. Together these results show a surprising level of divergence of the host response to pathogenic and non-pathogenic organisms associated with oral infections, and supports a dominant effect of P. intermedia in polymicrobial endodontic infections.
    Preview · Article · Jul 2015 · PLoS ONE
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    Tommy Hui · Esben S Sørensen · Susan R Rittling
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    ABSTRACT: Osteopontin (OPN) is a ligand for the α4 integrin, but the physiological importance of this binding is not well understood. Here, we have assessed the effect of posttranslational modifications on OPN binding to the α4 integrin on cultured human leukocyte cell lines, and compared OPN interaction with α4 integrin to that of VCAM and fibronectin. Jurkat cells, whose α4 integrins are inherently activated, adhered to different preparations of OPN in the presence of Mn(2+): the EC50 of adhesion was not affected by phosphorylation or glycosylation status. Thrombin cleavage of OPN at the C-terminus of the α4 integrin binding site also did not affect binding affinity. THP-1 cells express a low affinity conformation of the integrin and adhered to OPN only in the presence of Mn(2+) plus PMA or an activating antibody. This was in contrast to VCAM and fibronectin: THP-1 cells adhered to these ligands without integrin activation. Studies with ligand induced binding site antibodies demonstrated that the SVVYGLR peptide of OPN bound to the α4 integrin with a similar affinity as the LDV peptide of fibronectin, suggesting that a high off-rate is responsible for the reduced binding of OPN to the low affinity forms of this integrin. Together, the results suggest OPN has very low affinity for the α4 integrin on human leukocytes under physiological conditions. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Nov 2014 · Matrix biology: journal of the International Society for Matrix Biology
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    ABSTRACT: Endodontic infections, in which oral bacteria access the tooth pulp chamber, are common and do not resolve once established. To investigate the effects of these infections on the innate immune response, we established a mouse subcutaneous chamber model, where a mixture of four oral pathogens commonly associated with these infections (endodontic pathogens [EP]), i.e., Fusobacterium nucleatum, Streptococcus intermedius, Parvimonas micra, and Prevotella intermedia, was inoculated into subcutaneously implanted titanium chambers. Cells that infiltrated the chamber after these infections were primarily neutrophils; however, these neutrophils were unable to control the infection. Infection with a nonpathogenic oral bacterial species, Streptococcus mitis, resulted in well-controlled infection, with bacterial numbers reduced by 4 to 5 log units after 7 days. Propidium iodide (PI) staining of the chamber neutrophils identified three distinct populations: neutrophils from EP-infected chambers were intermediate in PI staining, while cells in chambers from mice infected with S. mitis were PI positive (apoptotic) or negative (live). Strikingly, neutrophils from EP-infected chambers were severely impaired in their ability to phagocytose and to generate reactive oxygen species in vitro after removal from the chamber compared to cells from S. mitis-infected chambers. The mechanism of neutrophil impairment was necrotic cell death as determined by morphological analyses. P. intermedia alone could induce a similar neutrophil phenotype. We conclude that the endodontic pathogens, particularly P. intermedia, can efficiently disable and kill infiltrating neutrophils, allowing these infections to become established. These results can help explain the persistence of endodontic infections and demonstrate a new virulence mechanism associated with P. intermedia.
    Preview · Article · Jul 2014 · Infection and Immunity
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    ABSTRACT: Rodent hindlimb unloading (HU) by tail-suspension is a model to investigate disuse-induced bone loss in vivo. Previously, we have shown that osteopontin (OPN, also known as Spp1) is required for unloading-induced bone loss. However, how unloading affects OPN expression in the body is not fully understood. Here, we examined OPN expression in peripheral blood of mice subjected to HU. Real-time RT-PCR analysis indicated that OPN expression is increased in circulating peripheral blood cells. This HU-induced increase in OPN mRNA expression was specific in circulating peripheral blood cells, as OPN was not increased in the blood cells in bone marrow. HU-induced enhancement in OPN expression in peripheral blood cells was associated with an increase in the fraction of monocyte/macrophage lineage cells in the peripheral blood. In contrast, HU decreased the fraction size of B-lymphocytes in the peripheral blood. We further examined if B-lymphogenesis is affected in the mice deficient for osteopontin subjected to HU. In bone marrow, HU decreased the population of the B-lymphocyte lineage cells significantly, whereas it did not alter the population of monocyte/macrophage lineage cells. HU also increased the cells in T-lymphocyte lineage in bone marrow. Interestingly, these changes were observed similarly both in OPN-deficient and wild-type mice. These results indicate for the first time that HU increases OPN expression in circulating cells and suppresses bone marrow B-lymphogenesis.
    No preview · Article · May 2014 · Journal of Bone and Mineral Metabolism
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    S R Rittling · P L Wejse · K Yagiz · G A Warot · T Hui
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    ABSTRACT: Background: The integrin-binding protein osteopontin is strongly associated with tumour development, yet is an abundant dietary component as a constituent of human and bovine milk. Therefore, we tested the effect of orally administered osteopontin (o-OPN) on the development of subcutaneous tumours in mice. Methods: Bovine milk osteopontin was administered in drinking water to tumour-bearing immune-competent mice. Tumour growth, proliferation, necrosis, apoptosis and blood vessel size and number were measured. Expression of the α9 integrin was determined. Results: o-OPN suppressed tumour growth, increased the extent of necrosis, and induced formation of abnormally large blood vessels. Anti-OPN reactivity detected in the plasma of OPN-null mice fed OPN suggested that tumour-blocking peptides were absorbed during digestion, but the o-OPN effect was likely distinct from that of an RGD peptide. Expression of the α9 integrin was detected on both tumour cells and blood vessels. Potential active peptides from the α9 binding site of OPN were identified by mass spectrometry following in vitro digestion, and injection of these peptides suppressed tumour growth. Conclusions: These results suggest that peptides derived from o-OPN are absorbed and interfere with tumour growth and normal vessel development. o-OPN-derived peptides that target the α9 integrin are likely involved.
    Preview · Article · Jan 2014 · British Journal of Cancer
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    ABSTRACT: The overexpression of osteopontin is associated with various inflammatory liver diseases. Interestingly, each of these diseases is also associated with IL-17 expression. Therefore, we sought to determine whether there is any mechanistic link between osteopontin and IL-17. Herein we show that IL-17 and osteopontin levels were significantly increased in patients with chronic hepatitis B. We found that IL-17 and osteopontin levels increased similarly in mice with concanavalin A-induced hepatitis. Both osteopontin- and IL-17-deficient mice were resistant to concanavalin A-induced hepatic injury. In addition, osteopontin markedly induced IL-17 expression by leukocytes (from humans and mice). This effect could be blocked by a specific antibody against osteopontin. β3 integrin (one of the osteopontin receptors) was critically involved in the induction of IL-17 production by osteopontin. Osteopontin-induced IL-17 expression was mediated through the p38, JNK, and NF-κB pathways. These findings suggest that osteopontin regulates IL-17 production during the pathogenesis of hepatitis and provide new evidence for the critical roles of osteopontin and IL-17 in hepatitis.
    Full-text · Article · Jul 2012 · Cytokine
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    ABSTRACT: Apoptosis of chondrocytes in articular cartilage has been observed in rheumatoid arthritis patients. However, molecules involved in such chondrocyte apoptosis in arthritic joints have not been fully understood. We previously observed that apoptosis of chondrocytes is enhanced in a murine arthritis model induced by injection with anti-type II collagen antibodies and lipopolysaccharide (mAbs/LPS), and osteopontin (OPN) deficiency suppresses chondrocyte apoptosis in this arthritis model in vivo. To understand how OPN deficiency renders resistance against chondrocyte apoptosis, we examined the cellular basis for this protection. Chondrocytes were prepared from wild-type and OPN-deficient mouse ribs, and tumor necrosis factor (TNF)-α-induced cell death was examined based on lactate dehydrogenase (LDH) release assay and TUNEL assay. TNF-α treatment induced LDH release in wild-type chondrocytes, while OPN deficiency suppressed such LDH release in the cultures of these cells. TNF-α-induced increase in the number of TUNEL-positive cells was observed in wild-type chondrocytes, while OPN deficiency in chondrocytes suppressed the TNF-α induction of TUNEL-positive cells. OPN deficiency suppressed TNF-α-induced increase in caspase-3 activity in chondrocytes in culture. Furthermore, OPN overexpression in chondrocytes enhanced TNF-α-induced apoptosis. These results indicated that the presence of OPN in chondrocytes is involved in the susceptibility of these cells to TNF-α-induced apoptosis.
    Full-text · Article · Feb 2012 · Cartilage
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    ABSTRACT: The sympathetic nervous system suppresses bone mass by mechanisms that remain incompletely elucidated. Using cell-based and murine genetics approaches, we show that this activity of the sympathetic nervous system requires osteopontin (OPN), a cytokine and one of the major members of the noncollagenous extracellular matrix proteins of bone. In this work, we found that the stimulation of the sympathetic tone by isoproterenol increased the level of OPN expression in the plasma and bone and that mice lacking OPN (OPN-KO) suppressed the isoproterenol-induced bone loss by preventing reduced osteoblastic and enhanced osteoclastic activities. In addition, we found that OPN is necessary for changes in the expression of genes related to bone resorption and bone formation that are induced by activation of the sympathetic tone. At the cellular level, we showed that intracellular OPN modulated the capacity of the β2-adrenergic receptor to generate cAMP with a corresponding modulation of cAMP-response element binding (CREB) phosphorylation and associated transcriptional events inside the cell. Our results indicate that OPN plays a critical role in sympathetic tone regulation of bone mass and that this OPN regulation is taking place through modulation of the β2-adrenergic receptor/cAMP signaling system.
    Full-text · Article · Oct 2011 · Proceedings of the National Academy of Sciences
  • Susan R Rittling
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    ABSTRACT: The secreted phosphorylated protein osteopontin (OPN) is expressed in a variety of tissues and bodily fluids, and is associated with pathologies including tissue injury, infection, autoimmune disease and cancer. Macrophages are ubiquitous, heterogeneous cells that mediate aspects of cell and tissue damage in all these pathologies. Here, the role of OPN in macrophage function is reviewed. OPN is expressed in macrophage cells in multiple pathologies, and the regulation of its expression in these cells has been described in vitro. The protein has been implicated in multiple functions of macrophages, including cytokine expression, expression of inducible nitric oxide synthase, phagocytosis and migration. Indeed, the role of OPN in cells of the macrophage lineage might underlie its physiological role in many pathologies. However, there are numerous instances where the published literature is inconsistent, especially in terms of OPN function in vitro. Although the heterogeneity of OPN and its receptors, or of macrophages themselves, might underlie some of these inconsistencies, it is important to understand the role of OPN in macrophage biology in order to exploit its function therapeutically.
    No preview · Article · Oct 2011 · Expert Reviews in Molecular Medicine
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    ABSTRACT: Parathyroid hormone/parathyroid hormone-related protein receptor (PPR) signaling is known to be involved in tooth development. In bone, extracellular matrix protein osteopontin (OPN) is a negative regulator of PPR signaling in bone formation. However, the role of OPN in modulation of PPR action in tooth development is not understood. Therefore, we examined the tooth in double mutant mice. Constitutively active PPR was expressed specifically in the odontoblasts and osteoblasts (caPPR-tg) in the presence or absence of OPN. Radiographic analysis indicated that the length of the third molar (M3) and the incisor was decreased in the caPPR-tg mice compared to wild type, and such reduction in molar and incisor length was further enhanced in the absence of OPN (caPPR-tg OPN-KO). With respect to histology of incisors, caPPR-tg induced high cellularity and irregularity in odontoblastic shape and this was enhanced by the absence of OPN. These morphological observations suggest that OPN modulates PPR signaling that are involved in tooth formation.
    No preview · Article · Jun 2011 · Tissue and Cell
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    ABSTRACT: Renal ischemia reperfusion injury (IRI) occurs after reduced renal blood flow and is a major cause of acute injury in both native and transplanted kidneys. Studies have shown diverse cell types in both the innate and the adaptive immune systems participate in kidney IRI as dendritic cells, macrophages, neutrophils, B cells, CD4(+) NK(+) cells, and CD4(+) T cells all contribute to this form of injury. Recently, we have found that NK cells induce apoptosis in tubular epithelial cells (TECs) and also contribute to renal IRI. However, the mechanism of NK cell migration and activation during kidney IRI remains unknown. In this study, we have identified that kidney TECs express a high level of osteopontin (OPN) in vitro and in vivo. C57BL/6 OPN-deficient mice have reduced NK cell infiltration with less tissue damage compared with wild-type C57BL/6 mice after ischemia. OPN can directly activate NK cells to mediate TEC apoptotic death and can also regulate chemotaxis of NK cells to TECs. Taken together, our study's results indicate that OPN expression by TECs is an important factor in initial inflammatory responses that involves NK cells activity in kidney IRI. Inhibiting OPN expression at an early stage of IRI may be protective and preserve kidney function after transplantation.
    Full-text · Article · Jul 2010 · The Journal of Immunology
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    ABSTRACT: To investigate the molecular mechanisms underlying particle-induced osteolysis, we focused on osteopontin (OPN), a cytokine and cell-attachment protein that is associated with macrophage chemoattractant and osteoclast activation. We compared OPN protein levels in human periprosthetic osteolysis tissues with those in osteoarthritis (OA) synovial tissues. To investigate the functions of OPN during particle-induced osteolysis in vivo, titanium particles were implanted onto the calvaria of OPN-deficient mice and their wild-type (WT) littermates. Mice were killed on day 10 and evaluated immunohistologically. The effects of OPN deficiency on the secretion of inflammatory cytokines were examined using cultured bone marrow-derived macrophages (BMMs). BMMs from OPN-deficient and WT mice were cultured with titanium particles for 12 hours, and the concentrations of inflammatory cytokines in the conditioned media were measured by enzyme-linked immunosorbent assay. Expression of OPN protein was enhanced in human periprosthetic osteolysis tissues as compared with OA synovial tissues. In the particle-induced model of osteolysis of the calvaria, bone resorption was significantly suppressed by OPN deficiency via inhibition of osteoclastogenesis, whereas an inflammatory reaction was observed regardless of the genotype. Results of immunostaining indicated that OPN protein was highly expressed in the membrane and bone surface at the area of bone resorption in WT mice. When BMMs were exposed to titanium particles, the concentration of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1alpha (IL-1alpha), IL-1beta, and IL-6, as well as chemotactic factors, such as monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha, in the conditioned medium were significantly reduced by OPN deficiency. Whereas phagocytic activity of BMMs was not attenuated by OPN deficiency, phagocytosis-mediated NF-kappaB activation was impaired in OPN-deficient BMMs. These data indicated that OPN was implicated in the development of particle-induced osteolysis via the orchestration of pro-/antiinflammatory cytokines secreted from macrophages. OPN plays critical roles in wear debris-induced osteolysis, suggesting that OPN is a candidate therapeutic target for periprosthetic osteolysis.
    Full-text · Article · May 2010 · Arthritis & Rheumatology
  • Susan R. Rittling
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    ABSTRACT: Osteopontin (OPN) is a secreted phosphoprotein that is found in high levels in bone tissues. Expression of OPN is required for optimal bone resorption under pathological conditions, with a notable exception being in the case of bone metastases, where OPN deficiency does not affect tumor-associated bone loss. It is suggested that tumor cells are the primary source of CSF-1 in tumors metastatic to the bone, and that CSF-1 and integrin signaling pathways crosstalk in osteoclasts in the vicinity of tumors expressing CSF-1. Thus, high-level expression of CSF-1 in tumor cells may override the osteoclast defect seen in OPN-deficient mice. Key wordsosteopontin-bone metastasis-CSF-1-integrin-signaling
    No preview · Chapter · Dec 2009
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    ABSTRACT: Osteopontin (OPN) is a secreted phosphoglycoprotein with a wide range of functions, and is involved in various pathophysiological conditions. However, the role of OPN in IgE and Th2-associated allergic responses remains incompletely defined. The aim of this study was to elucidate the role of OPN in systemic allergen sensitization in mice. When compared with OPN(+/+) mice, significantly increased levels of OVA-induced IgE were found in OPN(-/-) mice. OPN(-/-) DC demonstrated an increased capacity to enhance Th2 cytokine production in CD4+ T cells from sensitized OPN(+/+) mice. Furthermore, significantly reduced levels of IL-12p70 expression were seen in LPS-stimulated OPN(-/-) DC as compared with the WT DC, and the reduction was reversible by the addition of recombinant OPN (rOPN). rOPN was able to suppress OVA-induced IL-13 production in the cultures of CD4 and OPN(-/-) DC, but this inhibitory activity was neutralized by the addition of anti-IL-12 Ab. In addition, administration of rOPN in vivo suppressed OVA-specific IgE production; however, this suppressive effect was abrogated in IL-12-deficient mice. These results indicate that DC-derived OPN plays a regulatory role in the development of systemic allergen sensitization, which is mediated, at least in part, through the production of endogenous IL-12.
    Full-text · Article · Dec 2009 · European Journal of Immunology
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    ABSTRACT: Transforming growth factor-beta1 (TGF-beta1) is a crucial molecule for stimulation of breast cancer invasion and formation of bone metastases. The molecular mechanisms of how TGF-beta1 mediates these effects have yet to be completely determined. We have found that activating transcription factor-3 (ATF-3) is strongly stimulated and its level is sustained by TGF-beta1 in highly invasive and metastatic human breast cancer (MDA-MB231) and in mouse mammary pad tumor cells (r3T). ATF-3 is also overexpressed in human primary breast cancer tissue. Overexpression of ATF-3 increased normal human mammary epithelial cell number and DNA synthesis suggesting a role for ATF-3 in cell proliferation. The functional role of ATF-3 in breast cancer progression was determined by the RNA interference technique. Knockdown of ATF-3 by ATF-3 shRNA in MDA-MB231 cells decreased expression of cell cycle gene, cyclin A1 in MDA-MB231 cells. ATF-3 shRNA also decreased expression of an invasive and metastatic gene, matrix metalloproteinase-13 (MMP-13; collagenase-3) in these cells. Chromatin immunoprecipitation experiments identified the direct physical interaction of ATF-3 protein on the human MMP-13 promoter. Thus, the dysregulation of ATF-3 by TGF-beta1 is likely to activate cyclin A1 and MMP-13 genes in breast cancer cells and that would be key to the subsequent cancer cell invasion and metastasis.
    Full-text · Article · Oct 2009 · Journal of Cellular Biochemistry
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    ABSTRACT: To investigate the effects of loss of osteopontin (OPN) in the development of neovascularization in corneal stroma in mice. Cell culture study was also conducted to clarify the effects of OPN in transforming growth factor (TGF) beta1-driven cell signaling and expression of vascular endothelial growth factor (VEGF). Ocular fibroblasts from wild-type and OPN-null mice were used to study the role of OPN in TGFbeta1 signal and VEGF expression. The effect of the absence of OPN on corneal neovascularization was evaluated in mice. In ocular fibroblast culture, loss of OPN attenuated TGFbeta1 signals (Smad3 and p38) and reduced expression of VEGF. Loss of OPN attenuated neovascularization in corneal stroma in mice. OPN is involved in VEGF expression in cultured fibroblasts and is required for neovascularization in corneal stroma in vivo.
    Full-text · Article · Oct 2009 · Investigative ophthalmology & visual science
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    ABSTRACT: Endodontic infections are polymicrobial infections resulting in bone destruction and tooth loss. The host response to these infections is complex, including both innate and adaptive mechanisms. Osteopontin (OPN), a secreted, integrin-binding protein, functions in the regulation of immune responses and enhancement of leucocyte migration. We have assessed the role of OPN in the host response to endodontic infection using a well-characterized mouse model. Periapical bone loss associated with endodontic infection was significantly more severe in OPN-deficient mice compared with wild-type 3 weeks after infection, and was associated with increased areas of inflammation. Expression of cytokines associated with bone loss, interleukin-1alpha (IL-1alpha) and RANKL, was increased 3 days after infection. There was little effect of OPN deficiency on the adaptive immune response to these infections, as there was no effect of genotype on the ratio of bacteria-specific immunoglobulin G1 and G2a in the serum of infected mice. Furthermore, there was no difference in the expression of cytokines associated with T helper type 1/type2 balance: IL-12, IL-10 and interferon-gamma. In infected tissues, neutrophil infiltration into the lesion area was slightly increased in OPN-deficient animals 3 days after infection: this was confirmed by a significant increase in expression of neutrophil elastase in OPN-deficient samples at this time-point. We conclude that OPN has a protective effect on polymicrobial infection, at least partially because of alterations in phagocyte recruitment and/or persistence at the sites of infection, and that this molecule has a potential therapeutic role in polymicrobial infections.
    Full-text · Article · Sep 2009 · Immunology
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    ABSTRACT: Bone healing is a complex multi-step process, which depends on the position and size of the lesion, and on the mechanical stability of the wounded area. To address more specifically the mechanisms involved in cortical bone healing, we created drill-hole defects in the cortex of mouse femur, a lesion that triggers intramembranous repair, and compared the roles of bone sialoprotein (BSP) and osteopontin (OPN), two proteins of the extracellular matrix, in the repair process. Bone regeneration was analyzed by ex vivo microcomputerized X-ray tomography and histomorphometry of bones of BSP-deficient, OPN-deficient and wild-type mice. In all mouse strains, the cortical gap was bridged with woven bone within 2 weeks and no mineralized tissue was observed in the marrow. Within 3 weeks, lamellar cortical bone filled the gap. The amount and degree of mineralization of the woven bone was not affected by OPN deficiency, but cortical bone healing was delayed in BSP-deficient mice due to delayed mineralization. Gene expression studies showed a higher amount of BSP transcripts in the repair bone of OPN-deficient mice, suggesting a possible compensation of OPN function by BSP in OPN-null mice. Our data suggest that BSP, but not OPN, plays a role in primary bone formation and mineralization of newly formed bone during the process of cortical bone healing.
    No preview · Article · Sep 2009 · Bone
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    ABSTRACT: To investigate the role of osteopontin (OPN) in the development of osteoarthritis (OA) under in vivo and in vitro conditions. Both instability-induced and aging-associated OA models were generated using OPN-deficient (OPN-/-) and control wild-type (WT) mice. An in vitro cartilage degradation model was also used, to evaluate the effect of OPN on proteoglycan loss from joint cartilage. OPN deficiency exacerbated both aging-associated and instability-induced OA. Both structural changes and an increased loss of proteoglycan from cartilage tissue were augmented in the absence of OPN. OPN deficiency also led to the induction of matrix metalloproteinase 13 (MMP-13), which degrades a major component of the cartilage matrix protein type II collagen. Both the loss of proteoglycan and the induction of the collagen-degrading enzyme MMP-13 facilitated the development of OA. OPN plays a pivotal role in the progression of both instability-induced and aging-associated spontaneous OA. OPN is a critical intrinsic regulator of cartilage degradation via its effects on MMP-13 expression and proteoglycan loss.
    Full-text · Article · Aug 2009 · Arthritis & Rheumatology

Publication Stats

7k Citations
619.40 Total Impact Points


  • 2006-2015
    • Harvard University
      • Department of Developmental Biology
      Cambridge, Massachusetts, United States
  • 2006-2014
    • The Forsyth Institute
      Cambridge, Massachusetts, United States
  • 1992-2012
    • Rutgers, The State University of New Jersey
      • • Department of Cell Biology and Neuroscience
      • • Department of Genetics
      • • Division of Life Sciences
      Нью-Брансуик, New Jersey, United States
  • 2010
    • London Health Sciences Centre
      London, Ontario, Canada
  • 2007
    • Fenway Institute
      Boston, Massachusetts, United States
  • 2005
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2004
    • Hokkaido University
      • Department of Cardiovascular Medicine
      Sapporo-shi, Hokkaido, Japan
  • 2002
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States
  • 2001
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 1999-2001
    • Tokyo Medical and Dental University
      • Department of Molecular Pharmacology
      Edo, Tōkyō, Japan
    • State University of New York
      New York, New York, United States
  • 1993
    • Wistar Institute
      Filadelfia, Pennsylvania, United States
  • 1986-1987
    • Temple University
      Philadelphia, Pennsylvania, United States