K Johnson1, R Terkeltaub. 1. Veterans Affairs Medical Center, UCSD, La Jolla, CA 92161, USA.
Abstract
OBJECTIVE: In idiopathic chondrocalcinosis and in osteoarthritis (OA), increased extracellular PP(i) (ecPP(i)) promotes calcification. In chromosome 5p-associated familial chondrocalcinotic degenerative arthropathy, certain mutations in the membrane protein ANK may chronically raise ecPP(i) via enhanced PP(i) channeling. Therefore, we assessed if dysregulated wild-type ANK expression could contribute to pathogenesis of idiopathic degenerative arthropathy through elevated ecPP(i). DESIGN: Using cells with genetic alterations in expression of ANK and the PP(i)-generating nucleotide pyrophosphatase phosphodiestrase (NPP) PC-1, we examined how increased ANK expression elevates ecPPI, testing for codependent effects with PC-1. We also evaluated the effects of ANK expression on chondrocyte growth, matrix synthesis, and MMP-13 expression and we immunohistochemically examined ANK expression in situ in human knee OA cartilages. RESULTS: Using cells expressing defective ANK, as well as PC-1 knockout cells, we demonstrated that ANK required PC-1 (and vice versa) to raise ecPP(i) and that the major ecPP(i) regulator TGFbeta required both ANK and PC-1 to elevate ecPP(i). Upregulation of wild-type ANK by transfection in normal chondrocytes not only raised ecPP(i) 5-fold to approximately 100nM but also directly stimulated matrix calcification and inhibited collagen and sulfated proteoglycans synthesis. In addition, upregulated ANK induced chondrocyte MMP-13, an effect that also was stimulated within 2h by treatment of chondrocytes with 100nM PP(i) alone. Finally, ANK expression was upregulated in situ in human knee OA cartilages. CONCLUSION: Elevation of ecPP(i) by ANK critically requires the fraction of cellular PP(i) generated by PC-1. The upregulation of ANK expression in OA cartilage and the capacity of increased ANK expression to induce MMP-13 and to promote matrix loss suggest that increased ANK expression and ecPP(i) exert noxious effects in degenerative arthropathies beyond stimulation of calcification.
OBJECTIVE: In idiopathic chondrocalcinosis and in osteoarthritis (OA), increased extracellular PP(i) (ecPP(i)) promotes calcification. In chromosome 5p-associated familial chondrocalcinotic degenerative arthropathy, certain mutations in the membrane protein ANK may chronically raise ecPP(i) via enhanced PP(i) channeling. Therefore, we assessed if dysregulated wild-type ANK expression could contribute to pathogenesis of idiopathic degenerative arthropathy through elevated ecPP(i). DESIGN: Using cells with genetic alterations in expression of ANK and the PP(i)-generating nucleotide pyrophosphatase phosphodiestrase (NPP) PC-1, we examined how increased ANK expression elevates ecPPI, testing for codependent effects with PC-1. We also evaluated the effects of ANK expression on chondrocyte growth, matrix synthesis, and MMP-13 expression and we immunohistochemically examined ANK expression in situ in human knee OA cartilages. RESULTS: Using cells expressing defective ANK, as well as PC-1 knockout cells, we demonstrated that ANK required PC-1 (and vice versa) to raise ecPP(i) and that the major ecPP(i) regulator TGFbeta required both ANK and PC-1 to elevate ecPP(i). Upregulation of wild-type ANK by transfection in normal chondrocytes not only raised ecPP(i) 5-fold to approximately 100nM but also directly stimulated matrix calcification and inhibited collagen and sulfated proteoglycans synthesis. In addition, upregulated ANK induced chondrocyte MMP-13, an effect that also was stimulated within 2h by treatment of chondrocytes with 100nM PP(i) alone. Finally, ANK expression was upregulated in situ in human knee OA cartilages. CONCLUSION: Elevation of ecPP(i) by ANK critically requires the fraction of cellular PP(i) generated by PC-1. The upregulation of ANK expression in OA cartilage and the capacity of increased ANK expression to induce MMP-13 and to promote matrix loss suggest that increased ANK expression and ecPP(i) exert noxious effects in degenerative arthropathies beyond stimulation of calcification.
Authors: Barry L Gruber; Ana Rita Couto; Jácome Bruges Armas; Matthew A Brown; Kathleen Finzel; Robert A Terkeltaub Journal: J Clin Rheumatol Date: 2012-06 Impact factor: 3.517
Authors: M Zhang; H Wang; J Zhang; H Zhang; H Yang; X Wan; L Jing; L Lu; X Liu; S Yu; W Chang; M Wang Journal: Osteoarthritis Cartilage Date: 2015-12-31 Impact factor: 6.576