A K Rosenthal1, D Hempel, I V Kurup, I Masuda, L M Ryan. 1. The Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. akrose@mcw.edu
Abstract
OBJECTIVE: Extracellular inorganic pyrophosphate (ePPi) plays a key role in the regulation of normal and pathologic mineralization. The purpose of this work was to evaluate the role of P1 and P2 purine receptors in modulating ePPi production by articular chondrocytes. METHODS: Porcine cartilage explants and chondrocyte monolayers were cultured in the presence of P1 agonists, or a P2 agonist or antagonist and inhibitors of P2 signaling. Ambient media ePPi concentrations were measured after 48-96h. RESULTS: The P1 agonists NECA and CGS 21680 significantly decreased ePPi concentrations surrounding chondrocytes and cartilage explants. The P2 agonist, ADP, increased ePPi levels, and the P2 antagonist, suramin, decreased ePPi concentrations. Thapsigargin and 1,2 bis-(2-aminophenoxy)ethane-N,N,N'N'-tetra acetic acid (BAPTA), which dampen Ca(2+)-related P2 signaling, suppressed the response to ADP. CONCLUSIONS: Purine receptors are important regulators of ePPi production by chondrocytes. P1 receptor stimulation diminishes and P2 receptor stimulation enhances ePPi production. Alterations in receptor signaling or aberrations of extracellular purine nucleotide metabolism resulting in abnormal quantities or proportions of P1 and P2 receptor ligands could foster changes in ePPi production that in turn affect mineralization. We propose a homeostatic role for extracellular purine nucleotides and purine receptors in stabilizing ePPi concentrations.
OBJECTIVE: Extracellular inorganic pyrophosphate (ePPi) plays a key role in the regulation of normal and pathologic mineralization. The purpose of this work was to evaluate the role of P1 and P2purine receptors in modulating ePPi production by articular chondrocytes. METHODS: Porcine cartilage explants and chondrocyte monolayers were cultured in the presence of P1 agonists, or a P2 agonist or antagonist and inhibitors of P2 signaling. Ambient media ePPi concentrations were measured after 48-96h. RESULTS: The P1 agonists NECA and CGS 21680 significantly decreased ePPi concentrations surrounding chondrocytes and cartilage explants. The P2 agonist, ADP, increased ePPi levels, and the P2 antagonist, suramin, decreased ePPi concentrations. Thapsigargin and 1,2 bis-(2-aminophenoxy)ethane-N,N,N'N'-tetra acetic acid (BAPTA), which dampen Ca(2+)-related P2 signaling, suppressed the response to ADP. CONCLUSIONS:Purine receptors are important regulators of ePPi production by chondrocytes. P1 receptor stimulation diminishes and P2 receptor stimulation enhances ePPi production. Alterations in receptor signaling or aberrations of extracellular purine nucleotide metabolism resulting in abnormal quantities or proportions of P1 and P2 receptor ligands could foster changes in ePPi production that in turn affect mineralization. We propose a homeostatic role for extracellular purine nucleotides and purine receptors in stabilizing ePPi concentrations.
Authors: J Strehlau; M Pavlakis; M Lipman; M Shapiro; L Vasconcellos; W Harmon; T B Strom Journal: Proc Natl Acad Sci U S A Date: 1997-01-21 Impact factor: 11.205
Authors: F Rutsch; S Vaingankar; K Johnson; I Goldfine; B Maddux; P Schauerte; H Kalhoff; K Sano; W A Boisvert; A Superti-Furga; R Terkeltaub Journal: Am J Pathol Date: 2001-02 Impact factor: 4.307
Authors: Ivana Gadjanski; Supansa Yodmuang; Kara Spiller; Sarindr Bhumiratana; Gordana Vunjak-Novakovic Journal: Tissue Eng Part A Date: 2013-06-25 Impact factor: 3.845
Authors: Yael Nadel; Joanna Lecka; Yocheved Gilad; Gal Ben-David; Daniel Förster; Georg Reiser; Sarah Kenigsberg; Jean Camden; Gary A Weisman; Hanoch Senderowitz; Jean Sévigny; Bilha Fischer Journal: J Med Chem Date: 2014-05-30 Impact factor: 7.446