Johnson Kristen, Terkeltaub Robert
Rheumatology Section, San Diego Veterans Affairs Medical Center, University of California School of Medicine, VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
Front Biosci. 2005 Jan 1;10:988-97. doi: 10.2741/1593.
Physiologic levels of extracellular PPi, which suppresses hydroxyapatite crystal growth, must be maintained by articular chondrocytes and resident cells in many othee tissues in order to prevent pathologic calcification. However, extracellular PPi rises in articular cartilage in direct association with aging. Matrix supersaturation with PPi stimulates chondrocalcinosis manifesting as calcium pyrophosphate dihydrate (CPPD) crystal deposition. Extracellular PPi levels are normally held in check by balances in PPi generation by nucleotide pyrophosphatase phosphodiesterase (NPP/NTPPPH) activity relative to PPi degradation by pyrophosphatases, by balance effects of cytokines and growth factors, and by transport of PPi from the cell interior involving the multiple-pass transmembrane protein ANK. But these mechanisms become dysrgulated in aging and osteoarthritic (OA) cartilage and extracellular PPi excess supervenes, mediated in large part by upregulated NPP1 and ANK expression in articular cartilage. Conversely, NPP1 and ANK deficiency states were recently linked to phenotypically similar forms of spontaneous soft tissue calcification with hydroxyapatite (HA). Here, we focus on recent advances in understanding of PPi metabolism and NPP1 and ANK function pertinent to the pathogenesis of pathologi matrix calcification in articular cartilage.
细胞外焦磷酸（PPi）的生理水平可抑制羟基磷灰石晶体生长，关节软骨细胞和许多其他组织中的驻留细胞必须维持这一水平，以防止病理性钙化。然而，随着年龄增长，关节软骨中的细胞外PPi水平会直接升高。PPi导致的基质过饱和会引发软骨钙质沉着症，表现为二水焦磷酸钙（CPPD）晶体沉积。细胞外PPi水平通常通过核苷酸焦磷酸酶磷酸二酯酶（NPP/NTPPPH）的PPi生成活性与焦磷酸酶的PPi降解活性之间的平衡、细胞因子和生长因子的平衡作用以及涉及多次跨膜蛋白ANK的细胞内PPi转运来控制。但在衰老和骨关节炎（OA）软骨中，这些机制会失调，细胞外PPi过量出现，这在很大程度上是由关节软骨中NPP1和ANK表达上调介导的。相反，最近发现NPP1和ANK缺乏状态与表型相似的羟基磷灰石（HA）自发性软组织钙化形式有关。在这里，我们重点关注在理解与关节软骨病理性基质钙化发病机制相关的PPi代谢以及NPP1和ANK功能方面的最新进展。
