Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis

Yamamoto, Norikazu; Sakai, Fumihiko; Kawa, Shigeyuki; Morimoto, Junko; Kimura, Chiemi; Yamazaki, Harumi; Okazaki, Ikuko; Seki, Nobuo; Fujii, Takashi; Uede, Toshimitsu

doi:10.1172/jci200317778

Cited by 88 publications

(155 citation statements)

References 38 publications

(19 reference statements)

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“…OPN is classified not only as an ECM component but also as a cytokine and is involved in various physiologic and pathologic conditions (13,(35)(36)(37)(38). With regard to the association of OPN with cartilage degradation, it has been shown that the expression of OPN protein and mRNA increases along with the severity of OA (22).…”

Section: Discussionmentioning

confidence: 99%

Accelerated development of aging‐associated and instability‐induced osteoarthritis in osteopontin‐deficient mice

Matsui¹,

Iwasaki²,

Kawa³

et al. 2009

Arthritis & Rheumatism

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Objective. To investigate the role of osteopontin (OPN) in the development of osteoarthritis (OA) under in vivo and in vitro conditions.Methods. Both instability-induced and agingassociated OA models were generated using OPNdeficient (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.Results. OPN deficiency exacerbated both agingassociated 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.Conclusion. OPN plays a pivotal role in the progression of both instability-induced and agingassociated spontaneous OA. OPN is a critical intrinsic regulator of cartilage degradation via its effects on MMP-13 expression and proteoglycan loss.

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Section: Discussionmentioning

confidence: 99%

Accelerated development of aging‐associated and instability‐induced osteoarthritis in osteopontin‐deficient mice

Matsui¹,

Iwasaki²,

Kawa³

et al. 2009

Arthritis & Rheumatism

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“…The protein is secreted, variably phosphorylated and accumulates in bodily fluids; its strong affinity for hydroxyapatite leads to its accumulation in bone and other sites of mineralisation. While much of the molecule appears to lack secondary structure, a central region contains sequences that bind to as many as seven different integrins, including a v b 3 and b 5 , and a series of b 1 -containing integrins: the protein has a cryptic a 9 b 1 site that is functional only after protease cleavage, implying a unique role for OPN fragments (Yamamoto et al, 2003). Osteopontin interacts with cells through these integrins as well as through CD44, while an intracellular role for OPN has also been suggested wherein OPN binds CD44 on the inside face of the cell membrane (Sodek et al, 2000).…”

Section: Opn Functionmentioning

confidence: 99%

Role of osteopontin in tumour progression

2004

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Since its first identification as a transformation-associated protein, osteopontin (OPN) has been recognised as important in the processes of tumorigenicity and metastasis. Here, we review the evidence that OPN might be considered as a candidate prognostic marker in human cancer. In animal systems, evidence from cell injection experiments and genetically manipulated mice suggest an important but complex role for the protein in tumour progression. Moreover, studies in a variety of human cancers associate high levels of OPN expression in tumours or in blood with more advanced cancers. The mechanism of action of OPN in promoting cancer is still unclear, and we consider aspects of OPN biology that can complicate interpretation of human studies. Nevertheless, growing evidence supports a role for OPN as a potential prognostic factor for various human cancers.

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“…Thrombin cleavage may also alter the behavior of osteopontin (Yamamoto et al 2003). The thrombin cleavage site is near the integrin binding site in the osteopontin molecule, yet thrombin cleavage stimulates integrin binding in some cell types (Yokosaki et al 2005).…”

Section: The Effect Of De-phosphorylation and Thrombin Cleavage On Osmentioning

confidence: 99%

“…This stain also demonstrated fewer phosphates per milligram protein in recombinant osteopontin compared to milk osteopontin ( Figure 6). Taken together, these results suggest that osteopontin's ability to stimulate CPPD crystal formation is not fully dependent on its phosphorylation state.Thrombin cleavage may also alter the behavior of osteopontin (Yamamoto et al 2003). The thrombin cleavage site is near the integrin binding site in the osteopontin molecule, yet thrombin cleavage stimulates integrin binding in some cell types (Yokosaki et al 2005).…”

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confidence: 99%

Osteopontin promotes pathologic mineralization in articular cartilage

et al. 2007

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Calcium pyrophosphate dihydrate (CPPD) crystals are commonly found in osteoarthritic joint tissues, where they predict severe disease. Unlike other types of calcium phosphate crystals, CPPD crystals form almost exclusively in the pericellular matrix of damaged articular cartilage, suggesting a key role for the extracellular matrix milieu in their development. Osteopontin is a matricellular protein found in increased quantities in the pericellular matrix of osteoarthritic cartilage. Osteopontin modulates the formation of calcium-containing crystals in many settings. We show here that osteopontin stimulates ATP-induced CPPD crystal formation by chondrocytes in vitro. This effect is augmented by osteopontin's incorporation into extracellular matrix by transglutaminase enzymes, is only modestly affected by its phosphorylation state, and is inhibited by integrin blockers. Surprisingly, osteopontin stimulates transglutaminase activity in cultured chondrocytes in a dose responsive manner. As elevated levels of transglutaminase activity promote extracellular matrix changes that permit CPPD crystal formation, this is one possible mechanism of action. We demonstrate the presence of osteopontin in the pericellular matrix of chondrocytes adjacent to CPPD deposits and near active transglutaminases. Thus, osteopontin may play an important role in facilitating CPPD crystal formation in articular cartilage. KeywordsOsteopontin; Calcium pyrophosphate dihydrate; Transglutaminase; Osteoarthritis Pathologic matrix mineralization is a common occurrence in joints affected by late stage osteoarthritis. Of synovial fluids sampled at the time of knee replacement, for example, 60% contain pathologic calcium-containing crystals (Derfus et al. 2002). Both calcium pyrophosphate dihydrate (CPPD) and hydroxyapatite-like basic calcium phosphate (BCP) crystals occur in osteoarthritic joints. Although the role that calcium-containing crystals play in osteoarthritis is not fully understood, there is ample evidence to suggest that these crystals are active participants in joint damage. In vitro, calcium-containing crystals induce the release of catabolic cytokines and proteases from synovial cells and chondrocytes (Cheung 2001). Clinically, their presence predicts increased severity of joint damage and more rapid progression of joint destruction (Ledingham et al. 1993;Nalbant et al. 2003).Corresponding Author: Ann K. Rosenthal, MD Rheumatology Section/ cc-111W Zablocki VA Medical Center 5000 W. National Ave. Milwaukee, WI 53295-1000 TEL: 414-384-2000ann.rosenthal@med.va.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply ...

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Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis

Cited by 88 publications

References 38 publications

Accelerated development of aging‐associated and instability‐induced osteoarthritis in osteopontin‐deficient mice

Accelerated development of aging‐associated and instability‐induced osteoarthritis in osteopontin‐deficient mice

Role of osteopontin in tumour progression

Osteopontin promotes pathologic mineralization in articular cartilage

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