Musculoskeletal Research Center, Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, New York, NY, USA.
J Bone Miner Res. 2010 Aug;25(8):1771-83. doi: 10.1002/jbmr.60.
The progressive ankylosis gene (ank) encodes a transmembrane protein that transports intracellular inorganic pyrophosphate (PP(i)) to the extracellular milieu. ank/ank mice, which express a truncated nonfunctional ANK, showed a markedly reduced bone mass, bone-formation rate, and number of tartrate-resistant acid phosphatase-positive (TRAP(+)) multinucleated osteoclasts. ANK function deficiency suppressed osteoblastic differentiation of ank/ank bone marrow stromal cells, as indicated by the decrease in the expression of bone marker genes, including osterix, reduced alkaline phosphatase activity, and mineralization. Runx2 gene expression levels were not altered. Conversely, overexpression of ANK in the preosteoblastic cell line MC3T3-E1 resulted in increased expression of bone marker genes, including osterix. Whereas runx2 expression was not altered in ANK-overexpressing MC3T3-E1 cells, runx2 transcriptional activity was increased. Extracellular PP(i) or P(i) stimulated osteoblastogenic differentiation of MC3T3-E1 cells or partially rescued delayed osteoblastogenic differentiation of ank/ank bone marrow stromal cells. A loss of PP(i) transport function ANK mutation also stimulated osteoblastogenic differentiation of MC3T3-E1 cells. Furthermore, ANK function deficiency suppressed the formation of multinucleated osteoclasts from ank/ank bone marrow cells cultured in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor-kappaB ligand. In conclusion, ANK is a positive regulator of osteoblastic and osteoclastic differentiation events toward a mature osteoblastic and osteoclastic phenotype.
进行性关节强硬基因 (ank) 编码一种跨膜蛋白，可将细胞内无机焦磷酸盐 (PP(i)) 转运至细胞外环境。表达截断的无功能 ANK 的 ank/ank 小鼠表现出明显降低的骨量、骨形成率和抗酒石酸酸性磷酸酶阳性 (TRAP(+)) 多核破骨细胞数量。ANK 功能缺陷抑制 ank/ank 骨髓基质细胞的成骨细胞分化，表现为骨标志物基因的表达减少，包括osterix，碱性磷酸酶活性降低和矿化减少。Runx2 基因表达水平没有改变。相反，前成骨细胞系 MC3T3-E1 中 ANK 的过表达导致骨标志物基因，包括osterix 的表达增加。虽然 ANK 过表达的 MC3T3-E1 细胞中 runx2 表达没有改变，但 runx2 转录活性增加。细胞外 PP(i)或 P(i)刺激 MC3T3-E1 细胞的成骨细胞分化，或部分挽救 ank/ank 骨髓基质细胞成骨细胞分化延迟。ANK 转运功能丧失的 PP(i)突变也刺激 MC3T3-E1 细胞的成骨细胞分化。此外，ANK 功能缺陷抑制了巨噬细胞集落刺激因子和核因子-kappaB 受体激活剂配体存在下培养的 ank/ank 骨髓细胞中多核破骨细胞的形成。总之，ANK 是成骨细胞和成骨细胞分化事件向成熟成骨细胞和破骨细胞表型的正向调节剂。
