Lack of Requirement of Osteopontin for Inflammation, Bone Erosion, and Cartilage Damage in the K/BxN Model of Autoantibody-Mediated Arthritis

Joslin Diabetes Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02215, USA.
Arthritis & Rheumatology (Impact Factor: 7.76). 08/2004; 50(8):2685-94. DOI: 10.1002/art.20381
Source: PubMed


Osteopontin (OPN) is a secreted glycoprotein involved in a range of physiologic processes, including inflammation, immunity mediated by Th1 cells, and bone remodeling. It is expressed in the joints of rheumatoid arthritis patients and has been the subject of conflicting reports concerning its role in arthritis induced by antibodies against type II collagen. This study assessed the role of OPN in the K/BxN serum-transfer model of autoantibody-induced arthritis.
Expression of OPN gene transcripts was assessed by microarray analysis of ankle RNA taken at 6 time points after transfer of K/BxN serum. OPN-sufficient or OPN-deficient littermates backcrossed for 10 generations onto the C57BL/6 genetic background were given K/BxN serum. Arthritis severity was measured by ankle thickening and a clinical index. Hind limb sections were stained with hematoxylin and eosin or toluidine blue and scored for inflammation, cartilage damage, and bone erosion.
OPN messenger RNA transcripts progressively increased in ankle joints during the course of K/BxN serum-transferred arthritis. OPN-deficient mice receiving K/BxN serum developed arthritis with kinetics and clinical severity comparable with those of OPN-sufficient littermates. Histologic assessment of arthritic joints from OPN-deficient mice revealed synovial hyperplasia, pannus formation, mononuclear cell infiltration, bone erosion, cartilage damage at sites adjacent to and distal from pannus invasion, and tartrate-resistant acid phosphatase-positive multinucleated cells at sites of bone erosion. Histopathologic scoring demonstrated comparable levels of inflammation, cartilage damage, and bone erosion in OPN-sufficient and OPN-deficient mice.
OPN does not have a required role in inflammation, bone erosion, and cartilage damage in the K/BxN serum-transfer model.

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Available from: Allison R Pettit, Oct 09, 2015
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    • "Other pro-inflammatory factors in antibody-mediated arthritis – which may be generated by osteoblasts in a GC-dependent way – are urokinase-type plasminogen activator (u-PA) [41-43], matrix metalloproteinases (MMP) [18,43] and macrophage migration inhibitory factor (MIF) [44-46]. Osteopontin and IL-6 are rather unlikely to be responsible because they play no essential role in K/BxN arthritis [16,37]. "
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    ABSTRACT: The role of endogenous glucocorticoids (GC) in the initiation and maintenance of rheumatoid arthritis (RA) remains unclear. We demonstrated previously that disruption of GC signalling in osteoblasts results in a profound attenuation of K/BxN serum-induced arthritis, a mouse model of RA. To determine whether or not the modulation of the inflammatory response by osteoblasts involves T cells, we studied the effects of disrupted osteoblastic GC-signalling in the T cell-dependent model of antigen-induced arthritis (AIA). Acute arthritis was induced in pre-immunised 11-week-old male 11beta-hydroxysteroid dehydrogenase type 2 transgenic (tg) mice and their wild-type (WT) littermates by intra-articular injection of methylated bovine serum albumine (mBSA) into one knee joint. Knee diameter was measured every 1-2 days until euthanasia on day 14 post injection. In a separate experiment, arthritis was maintained for 28 days by weekly reinjections of mBSA. Tissues were analysed by histology, histomorphometry and microfocal-computed tomography. Serum cytokines levels were determined by multiplex suspension array. In both short and long term experiments, arthritis developed in tg and WT mice with no significant difference between both groups. Histological indices of inflammation, cartilage damage and bone erosion were similar in tg and WT mice. Bone volume and turnover at the contralateral tibia and systemic cytokine levels were not different. Acute murine AIA is not affected by a disruption in osteoblastic GC signalling. These data indicate that osteoblasts do not modulate the T cell-mediated inflammatory response via a GC-dependent pathway.
    BMC Musculoskeletal Disorders 02/2014; 15(1):31. DOI:10.1186/1471-2474-15-31 · 1.72 Impact Factor
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    • "It was found that its level is increased in RA., Its exact role in RA is however still unclear. It was noticed by one group that OPN knocked out mice were protected against RA [114], yet another group of researchers failed to produce the same conclusions [115]. Overexpression of OPN is also noticed in a variety of cancers, including lung, breast, colorectal and stomach cancer. "
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    ABSTRACT: The current standard of care (SOC) for hepatitis C virus (HCV) infection is the combination of pegylated interferon (PEG-IFN), Ribavirin and protease inhibitor for HCV genotype 1. Nevertheless, this treatment is successful only in 70-80% of the patients. In addition, the treatment is not economical and is of immense physical burden for the subject. It has been established now, that virus-host interactions play a significant role in determining treatment outcomes. Therefore identifying biological markers that may predict the treatment response and hence treatment outcome would be useful. Both IFN and Ribavirin mainly act by modulating the immune system of the patient. Therefore, the treatment response is influenced by genetic variations of the human as well as the HCV genome. The goal of this review article is to summarize the impact of recent scientific advances in this area regarding the understanding of human and HCV genetic variations and their effect on treatment outcomes. Google scholar and PubMed have been used for literature research. Among the host factors, the most prominent associations are polymorphisms within the region of the interleukin 28B (IL28B) gene, but variations in other cytokine genes have also been linked with the treatment outcome. Among the viral factors, HCV genotypes are noteworthy. Moreover, for sustained virological responses (SVR), variations in core, p7, non-structural 2 (NS2), NS3 and NS5A genes are also important. However, all considered single nucleotide polymorphisms (SNPs) of IL28B and viral genotypes are the most important predictors for interferon based therapy of HCV infection.
    Virology Journal 10/2013; 10(1):299. DOI:10.1186/1743-422X-10-299 · 2.18 Impact Factor
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    • "Mitigation of experimental autoimmune encephalomyelitis and collagen-induced arthritis have been reported in the absence of osteopontin, although the latter finding is controversial and has not been observed by others (38–41). Moreover, the serum transfer model of arthritis is not altered by the absence of osteopontin (39). From these data, it is evident, however, that the interaction of osteopontin with CD44 is not a relevant factor for arthritic bone erosion. "
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    ABSTRACT: Chronic inflammation is a major trigger of local and systemic bone loss. Disintegration of cell-matrix interaction is a prerequisite for the invasion of inflammatory tissue into bone. CD44 is a type I transmembrane glycoprotein that connects a variety of extracellular matrix proteins to the cell surface. Tumor necrosis factor (TNF) is a major inducer of chronic inflammation and its overexpression leads to chronic inflammatory arthritis. By generating CD44(-/-) human TNF-transgenic (hTNFtg) mice, we show that destruction of joints and progressive crippling is far more severe in hTNFtg mice lacking CD44, which also develop severe generalized osteopenia. Mutant mice exhibit an increased bone resorption due to enhanced number, size, and resorptive capacity of osteoclasts, whereas bone formation and osteoblast differentiation are not affected. Responsiveness of CD44-deficient osteoclasts toward TNF is enhanced and associated with increased activation of the p38 mitogen-activated protein kinase. These data identify CD44 as a critical inhibitor of TNF-driven joint destruction and inflammatory bone loss.
    Journal of Experimental Medicine 04/2005; 201(6):903-14. DOI:10.1084/jem.20040852 · 12.52 Impact Factor
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