A histological study of calcium pyrophosphate dihydrate crystal-deposition disease.

Ishikawa, Kôichirô; Masuda, Ikuko; Ohira, Takashi; Yokoyama, Mitsuru

doi:10.2106/00004623-198971060-00012

Cited by 62 publications

(30 citation statements)

References 24 publications

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“…CPPD crystals are rarely found in areas of normal articular cartilage matrix (Bjelle 1981), suggesting that alterations in matrix composition and/or ion composition are necessary for crystallization. Ishikawa et al demonstrated fragmented type II collagen fibers, loss of large proteoglycans, and increased levels of calcium-binding matricellular proteins in cartilage affected by CPPD crystal deposits (Ishikawa et al 1989;Masuda et al 1991). Matrix-modifying enzymes known as transglutaminases have also been implicated in CPPD crystal formation ).…”

Section: Nih Public Accessmentioning

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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Section: Nih Public Accessmentioning

confidence: 99%

Osteopontin promotes pathologic mineralization in articular cartilage

et al. 2007

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“…But in OA, foci of articular chondrocyte hypertrophy develop, typically near sites of cartilage surface lesions (8,9). Chondrocyte hypertrophy in OA may function partly to modulate matrix remodeling and repair (10) and partly to promote calcification, as hypertrophic chondrocytes are commonly co-localized with deposits of hydroxyapatite and calcium pyrophosphate dihydrate crystals in the disease (11). Significantly, deposits of hydroxyapatite and calcium pyrophosphate dihydrate crystals crystals can stimulate intra-articular inflammation and further damage to cartilage in OA (12,13).…”

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confidence: 99%

Distinct Transglutaminase 2-independent and Transglutaminase 2-dependent Pathways Mediate Articular Chondrocyte Hypertrophy

Johnson

Etten

Nanda

et al. 2003

Journal of Biological Chemistry

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Altered chondrocyte differentiation, including development of chondrocyte hypertrophy, mediates osteoarthritis and pathologic articular cartilage matrix calcification. Similar changes in endochondral chondrocyte differentiation are essential for physiologic growth plate mineralization. In both articular and growth plate cartilages, chondrocyte hypertrophy is associated with up-regulated expression of certain protein-crosslinking enzymes (transglutaminases (TGs)) including the unique dualfunctioning TG and GTPase TG2. Here, we tested if TG2 directly mediates the development of chondrocyte hypertrophic differentiation. To do so, we employed normal bovine chondrocytes and mouse knee chondrocytes from recently described TG2 knockout mice, which are phenotypically normal. We treated chondrocytes with the osteoarthritis mediator IL-1␤, with the all-trans form of retinoic acid (ATRA), which promotes endochondral chondrocyte hypertrophy and pathologic calcification, and with C-type natriuretic peptide, an essential factor in endochondral development. IL-1␤ and ATRA induced TG transamidation activity and calcification in wild-type but not in TG2 (؊/؊) mouse knee chondrocytes. In addition, ATRA induced multiple features of hypertrophic differentiation (including type X collagen, alkaline phosphatase, and MMP-13), and these effects required TG2. Significantly, TG2 (؊/؊) chondrocytes lost the capacity for ATRA-induced expression of Cbfa1, a transcription factor necessary for ATRA-induced chondrocyte hypertrophy. Finally, C-type natriuretic peptide, which did not modulate TG activity, comparably promoted Cbfa1 expression and hypertrophy (without associated calcification) in TG2 (؉/؉) and TG2 (؊/؊) chondrocytes. Thus, distinct TG2-independent and TG2-dependent mechanisms promote Cbfa1 expression, articular chondrocyte hypertrophy, and calcification. TG2 is a potential site for intervention in pathologic calcification promoted by IL-1␤ and ATRA.In physiologic endochondral growth plate mineralization, chondrocytes undergo a multi-step differentiation process in which there is ordered progression from a resting to proliferative state followed by maturation to a terminally differentiated hypertrophic state (1). Hypertrophic chondrocytes are specialized to remodel and mineralize their matrix (2). For example, hypertrophic chondrocytes demonstrate up-regulated expression of MMP-13, a mediator of matrix degradation in osteoarthritis (OA) 1 (3). In addition, hypertrophic chondrocytes demonstrate altered patterns of collagen subtype generation that include stereotypic up-regulated type X collagen expression, and hypertrophic chondrocytes show markedly increased release of mineralization-competent secretory vesicles (2). In addition, hypertrophic chondrocytes demonstrate increased alkaline phosphatase (AP) activity and other alterations in the metabolism of P i and PP i (4, 6). In this context, P i and PP i mediate both calcification and growth plate organization (5), and P i promotes chondrocyte hypertrophy (6).In contrast to chondroc...

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“…7,8 Chondrocyte hypertrophy also is a frequent finding adjacent to articular cartilage deposits of calcium pyrophosphate dihydrate crystals. 9 One of the features of growth plate chondrocyte differentiation proposed to promote matrix calcification is increased expression of certain transglutaminases (TGases) (EC 2.3.2.13) in the hypertrophic zone. 10,11 The central effect of TGases is induction of posttranslational protein cross-linking in cells and in extracellular matrices.…”

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confidence: 99%