pyrophosphate and Osteoarthritis--Knee

The current study aimed to investigate the association of calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals in synovial fluid (SF) of patients with osteoarthritis (OA) with disease severity, clinical symptoms, and synovial inflammation. One-hundred-and-ten patients with knee OA completed the Western Ontario and McMaster Universities Arthritis Index (WOMAC) self-assessment questionnaire, the Lequesne algofunctional index survey, and the visual analogic scale forms; they also underwent power Doppler ultrasonography (PDUS) to assess synovial inflammation. Scanning electron microscopy (SEM) was used to detect SF crystals. SEM analyses uncovered CPP crystals in 26 patients (23.6%), BCP crystals in 24 patients (21.8%), and both types of crystals in 7 patients (6.3%). Categorizing patients according to SF crystal type, a strong association between BCP crystal presence, and higher WOMAC and Lequesne index scores has been uncovered. Classifying our patients according the severity Kellgre-Lawrence score, we found that the prevalence of CPP alone (27.8%) or in combination with BCP (11.1%) was higher in the late stage group with respect to the early one (CPP 21.6% and CPP + BCP 4.1%, respectively). The prevalence of BCP crystals alone was, instead, higher in the early (23%) with respect to the late group (19.4%). No association between the presence of crystals and the radiographic scores has been observed. Considering the growing evidence supporting a role of low-grade inflammation in OA pathogenesis, the results of this study suggest a role for calcium crystals in the development of the disease.

Topics: Aged; Aged, 80 and over; Calcium Phosphates; Diphosphates; Disease Progression; Female; Humans; Inflammation; Male; Microscopy, Electron, Scanning; Middle Aged; Osteoarthritis, Knee; Severity of Illness Index; Surveys and Questionnaires; Synovial Fluid; Ultrasonography, Doppler

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).. 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.. 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.. 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.

Topics: Animals; Calcinosis; Cartilage, Articular; Cells, Cultured; Chondrocytes; Collagen; Collagenases; Diphosphates; Extracellular Fluid; Humans; Immunohistochemistry; Knee Joint; Matrix Metalloproteinase 13; Mice; Mice, Inbred Strains; Osteoarthritis, Knee; Phosphoric Diester Hydrolases; Proteoglycans; Pyrophosphatases; Transfection; Transforming Growth Factor beta; Up-Regulation