Abstract
Calcium pyrophosphate (CPP) deposition disease (CPPD) is a form of CPP crystal-induced arthritis. A high concentration of extracellular pyrophosphate (ePPi) in synovial fluid is positively correlated with the formation of CPP crystals, and ePPi can be upregulated by ankylosis human (ANKH) and ectonucleotide pyrophosphatase 1 (ENPP1) and downregulated by tissue non-specific alkaline phosphatase (TNAP). However, there is currently no drug that eliminates CPP crystals. We explored the effects of the histone deacetylase (HDAC) inhibitors (HDACis) trichostatin A (TSA) and vorinostat (SAHA) on CPP formation. Transforming growth factor (TGF)-β1-treated human primary cultured articular chondrocytes (HC-a cells) were used to increase ePPi and CPP formation, which were determined by pyrophosphate assay and CPP crystal staining assay, respectively. Artificial substrates thymidine 5′-monophosphate p-nitrophenyl ester (p-NpTMP) and p-nitrophenyl phosphate (p-NPP) were used to estimate ENPP1 and TNAP activities, respectively. The HDACis TSA and SAHA significantly reduced mRNA and protein expressions of ANKH and ENPP1 but increased TNAP expression in a dose-dependent manner in HC-a cells. Further results demonstrated that TSA and SAHA decreased ENPP1 activity, increased TNAP activity, and limited levels of ePPi and CPP. As expected, both TSA and SAHA significantly increased the acetylation of histones 3 and 4 but failed to block Smad-2 phosphorylation induced by TGF-β1. These results suggest that HDACis prevented the formation of CPP by regulating ANKH, ENPP1, and TNAP expressions and can possibly be developed as a potential drug to treat or prevent CPPD.
Highlights
Introduction distributed under the terms andCalcium pyrophosphate (CPP) deposition disease (CPPD) is a manifestation of the abnormal accumulation of CPP crystals in a joint
Since we found that Histone deacetylase inhibitors (HDACis) could regulate ectonucleotide pyrophosphatase 1 (ENPP1) and tissue non-specific alkaline phosphatase (TNAP) gene expressions and enzyme activities, we examined whether the HDACis could decrease ePPi levels and enzyme activities, we examined whether the HDACis could decrease ePPi levels
We found that Transforming growth factor (TGF)-β1 markedly induced mRNA expressions of ankylosis human (ANKH) and ENPP1 but caused no significant change in TNAP mRNA expression in human primary cultured chondrocytes
Summary
Introduction distributed under the terms andCalcium pyrophosphate (CPP) deposition disease (CPPD) is a manifestation of the abnormal accumulation of CPP crystals in a joint. Extracellular pyrophosphate (ePPi), calcium, and extracellular matrix (ECM) are essential components of CPP crystal formation [3]. In CPPD patients, a high concentration of ePPi in the synovial fluid is mainly locally produced in joints [4]. Many diseases are characterized by high levels of ePPi in synovial fluid, including osteoarthritis (OA) with CPPD [5], hyperparathyroidism [6], hypomagnesemia [7], and hemochromatosis [8]. TNAP mR decreased mRNA expressions of ANKH and ENPP1 but increased TNAP mRNA expression expression in dose‐dependent manners compared to TGF‐β1‐treated cells in dose-dependent manners compared to TGF-β1-treated cells (Figure 1A). TSA dose-dependently inhibited protein expressions of protein pressions of TNAP expression (Figure 1B). ANKH and ENPP1 but increased TNAP expression (Figure 1B). SAHAOn the ot exhibitedboth similar trends of inhibiting both ANKHand andincreasing
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