Activation of annexin II and V expression, terminal differentiation, mineralization and apoptosis in human osteoarthritic cartilage

Kirsch, Thorsten; Swoboda, B.; Nah, Hyun Duck

doi:10.1053/joca.1999.0304

Cited by 201 publications

(203 citation statements)

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“…Previous reports have indicated that the biologic changes in articular chondrocytes during OA progression are similar to those of endochondral ossification (4,5). Investigators have found a sequential change of PTHrP localized in articular cartilage during the progression of inflammatory and degenerative arthritis (39).…”

Section: Discussionmentioning

confidence: 97%

“…In patients with OA, chondrocytes are known to be able to resume phenotypic changes such as those occurring in epiphyseal growth plates, where chondrocytes undergo the process of terminal differentiation from hypertrophy to mineral deposition to eventual apoptosis (4,5). Chondrocytes in OA express the marker proteins of hypertrophic chondrocytes, including annex-ins, alkaline phosphatase, and type X collagen, but not type II collagen (5).…”

mentioning

confidence: 99%

“…Chondrocytes in OA express the marker proteins of hypertrophic chondrocytes, including annex-ins, alkaline phosphatase, and type X collagen, but not type II collagen (5). Meanwhile, a feedback loop regulating endochondral ossification in growth plates involves parathyroid hormone-related peptide (PTHrP), Indian hedgehog (IHH), and Bcl-2.…”

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confidence: 99%

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Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Chang¹,

Chang²,

Hung³

et al. 2009

Arthritis & Rheumatism

100

120

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Objective. Parathyroid hormone 1-34 (PTH[1-34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone-related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1-34) inhibits terminal differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA).Methods. We studied the effect of PTH(1-34) on human articular chondrocytes with azacytidine (azaC)-induced terminal differentiation in vitro and on papaininduced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees.Results. AzaC induced terminal differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3-10 days of treatment with 10 nM PTH(1-34). SOX9 expression was not changed by either azaC or PTH(1-34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of terminal differentiation, but PTH(1-34) treatment did not reverse this effect. Furthermore, PTH(1-34) treatment reversed papaininduced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats.Conclusion. Our findings indicate that PTH(1-34) inhibits the terminal differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA.

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

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Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Chang¹,

Chang²,

Hung³

et al. 2009

Arthritis & Rheumatism

100

120

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“…This is further supported by the effect of thrombin on osteopontin, as the thrombin cleavage site is near the integrin binding locus of the protein. It is likely that chondrocytes are capable of assuming a phenotype similar to the hypertrophic phenotype responsible for bone formation in the growth plate, particularly in the setting of osteoarthritis (Kirsch et al 2000). Thus, it is not surprising that mechanisms of matrix mineralization in articular chondrocytes are similar to that of bone cells under certain conditions.…”

Section: Discussionmentioning

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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“…Chondrocyte hypertrophy is one of the characteristics of osteoarthritis (OA) (Kirsch et al 2000;Tchetina et al 2007; van der Kraan et al 2009), and therefore a potential therapeutic target. Also, various growth pathologies are associated with abnormal hypertrophy (Kuizon and Salusky 2004;Wilkie 2005;Zuscik et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Mechanics of chondrocyte hypertrophy

Donkelaar

Wilson

2011

Biomech Model Mechanobiol

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Chondrocyte hypertrophy is a characteristic of osteoarthritis and dominates bone growth. Intra-and extracellular changes that are known to be induced by metabolically active hypertrophic chondrocytes are known to contribute to hypertrophy. However, it is unknown to which extent these mechanical conditions together can be held responsible for the total magnitude of hypertrophy. The present paper aims to provide a quantitative, mechanically sound answer to that question. To address this aim requires a quantitative tool that captures the mechanical effects of collagen and proteoglycans, allows temporal changes in tissue composition, and can compute cell and tissue deformations. These requirements are met in our numerical model that is validated for articular cartilage mechanics, which we apply to quantitatively explain a range of experimental observations related to hypertrophy. After validating the numerical approach for studying hypertrophy, the model is applied to evaluate the direct mechanical effects of axial tension and compression on hypertrophy (Hueter-Volkmann principle) and to explore why hypertrophy is reduced in case of partially or fully compromised proteoglycan expression. Finally, a mechanical explanation is provided for the observation that chondrocytes do not hypertrophy when enzymatical collagen degradation is prohibited (S1Pcko knock-out mouse model). This paper shows that matrix turnover by metabolically active chondrocytes, together with externally applied mechanical conditions, can explain quantitatively the volumetric change of chondrocytes during hypertrophy. It provides a mechanistic explanation for the observation that collagen degradation results in chondrocyte hypertrophy, both under physiological and pathological conditions.

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Activation of annexin II and V expression, terminal differentiation, mineralization and apoptosis in human osteoarthritic cartilage

Cited by 201 publications

References 55 publications

Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats

Osteopontin promotes pathologic mineralization in articular cartilage

Mechanics of chondrocyte hypertrophy

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