Osteopontin Inhibits Mineral Deposition and Promotes Regression of Ectopic Calcification

Steitz, Susan A.; Speer, Mei Y.; McKee, Marc D.; Liaw, Lucy; Almeida, Manuela; Yang, Hongyan; Giachelli, Cecilia M.

doi:10.1016/s0002-9440(10)64482-3

Cited by 386 publications

(336 citation statements)

References 56 publications

(44 reference statements)

Supporting

Mentioning

299

Contrasting

Unclassified

Order By: Relevance

“…Thus, increased levels of osteopontin such as those that occur in osteoarthritic cartilage, could promote CPPD crystal formation. These findings contrast with the role typically assigned to osteopontin in most mineralization models, where it often acts as an inhibitor of crystal growth and/or nucleation (Steitz et al 2002;. Our work involves a different crystal type, and ample evidence suggests that factors that clearly inhibit calcium phosphate crystal formation may stimulate CPPD crystal formation.…”

Section: Discussioncontrasting

confidence: 65%

“…However, its role in mineral formation remains poorly understood and somewhat controversial. Osteopontin typically inhibits growth of calcium-containing crystals in models of bone mineralization and nephrolithiasis (Beshensky et al 2001;Steitz et al 2002). Similar effects have recently been demonstrated in a gel-based model of hydroxyapatite crystal formation (Gericke et al 2005).…”

Section: Nih Public Accessmentioning

confidence: 81%

See 1 more Smart Citation

Osteopontin promotes pathologic mineralization in articular cartilage

et al. 2007

View full text Add to dashboard Cite

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 ...

show abstract

Section: Discussioncontrasting

confidence: 65%

Section: Nih Public Accessmentioning

confidence: 81%

Osteopontin promotes pathologic mineralization in articular cartilage

et al. 2007

View full text Add to dashboard Cite

show abstract

“…35 The increased expression of OPN, a mineral-binding phosphoprotein abundant in several mineralized tissues, in both PXE and PXE-like can be considered a rescue response to MGP dysfunction. 36 OPN upregulation in mineralized aorta of MgpÀ/À mice has previously been proposed to act as a secondary, inducible, calcification inhibitor, which limits further mineralization. 3 In MgpÀ/À mice, OPN initiates removal of the mineral by macrophages.…”

Section: Vk-dependent Proteins In Pxe Patientsmentioning

confidence: 99%

Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome

Vanakker

Martin

Schurgers

et al. 2010

Laboratory Investigation

View full text Add to dashboard Cite

Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE.

show abstract

“…Furthermore, in the presence of MM cells, osteoclasts produce OPN, an angiogenic and immunoregulatory factor regarded as a metastasis gene (Asou et al, 2001, Ashkar et al, 2000. OPN has also been associated as a resorption stimulating factor, and a bone mineralization inhibitor, making its elevated production an even more serious factor in cases of bone lesions (Shapses et al, 2003, Steitz et al, 2002. Finally, contact itself between the osteoclasts and myeloma cells is also responsible for MM cell growth, mediated by VLA-4 and av/33-integrin adhesion (Abe et al, 2004).…”

Section: Myeloma Interactionmentioning

confidence: 99%