Linked deficiencies in extracellular PPi and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression
Linked deficiencies in extracellular PPi and osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expression
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DOI：
10.1359/jbmr.2003.18.6.994
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发表时间：
2003-06-01
影响因子：
6.2
通讯作者：
Terkeltaub, R
中科院分区：
文献类型：
--
作者：
Johnson, K;Goding, J;Terkeltaub, R
骨桥蛋白和PPi均抑制羟基磷灰石沉积。细胞外PPi缺乏导致自发性高钙化，然而未挑战的骨桥蛋白敲除小鼠只有轻微的矿化异常。我们报道细胞外PPi缺乏促进骨桥蛋白缺乏，而骨桥蛋白缺乏的纠正可防止高钙化，提示协同抑制羟基磷灰石沉积。核苷酸焦磷酸酶磷酸二酯酶（NPP）同工酶包括PC-1 （NPPI）部分功能产生PPI，生生性钙化抑制剂。PPi的转运受膜通道蛋白ANK的调控。踝关节畸形小鼠的自发关节软骨钙化、椎体皮质骨形成增加、外周关节和椎间骨性强直与PC-1缺乏和截断的ANK表达有关。为了评估PC-1、ANK和PPi如何调节钙化和细胞分化，我们研究了培养的PC-1（-/-）和踝关节小鼠颅骨成骨细胞。PC-1（-/-）成骨细胞表现出类似50%的NPP活性降低和与高钙化相关的细胞外PPi显著降低。这些异常可以通过转染PC-1而不是NPP同工酶B10/NPP3来恢复。PC-1（-/-）和踝关节培养的成骨细胞不仅表现出类似的细胞外PPi抑制和高钙化，而且骨桥蛋白（OPN）的表达也显著降低，OPN是另一种直接钙化抑制剂。可溶性PC-1（纠正细胞外PPi和OPN）和OPN本身（大于或等于15pg /ml）通过PC-1（-/-）和踝关节成骨细胞纠正高钙化。因此，细胞外PPi和OPN表达的相关调节作用介导PC-1和ANK调节钙化的能力。
Osteopontin and PPi both suppress hydroxyapatite deposition. Extracellular PPi deficiency causes spontaneous hypercalcification, yet unchallenged osteopontin knockout mice have only subtle mineralization abnormalities. We report that extracellular PPi deficiency promotes osteopontin deficiency and correction of osteopontin deficiency prevents hypercalcification, suggesting synergistic inhibition of hydroxyapatite deposition.Nucleotide pyrophosphatase phosphodiesterase (NPP) isozymes including PC-1 (NPPI) function partly to generate PPI, a physiologic calcification inhibitor. PPi transport is modulated by the membrane channel protein ANK. Spontaneous articular cartilage calcification, increased vertebral cortical bone formation, and peripheral joint and intervertebral ossific ankylosis are associated with both PC-1 deficiency and expression of truncated ANK in anklank mice. To assess how PC-1, ANK, and PPi regulate both calcification and cell differentiation, we studied cultured PC-1(-/-) and anklank mouse calvarial osteoblasts. PC-1(-/-) osteoblasts demonstrated similar to50% depressed NPP activity and markedly lowered extracellular PPi associated with hypercalcification. These abnormalities were rescued by transfection of PC-1 but not of the NPP isozyme B10/NPP3. PC-1(-/-) and anklank cultured osteoblasts demonstrated not only comparable extracellular PPi depression and hypercalcification but also marked reduction in expression of osteopontin (OPN), another direct calcification inhibitor. Soluble PC-1 (which corrected extracellular PPi and OPN), and OPN itself (greater than or equal to15 pg/ml), corrected hypercalcification by PC-1(-/-) and anklank osteoblasts. Thus, linked regulatory effects on extracellular PPi and OPN expression mediate the ability of PC-1 and ANK to regulate calcification.