Disthabanchong S, Radinahamed P, Stitchantrakul W, Hongeng S, Rajatanavin R
Division of Nephrology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Kidney Int. 2007 Feb;71(3):201-9. doi: 10.1038/sj.ki.5002035. Epub 2006 Dec 20.
Bone histology of distal renal tubular acidosis patients showed decreased bone formation with impaired bone matrix mineralization that is not entirely explained by an alteration in the mineral balance. Data from in vitro studies suggests a direct inhibitory effect of metabolic acidosis on osteoblast function. We investigated the effects of chronic metabolic acidosis on osteoblast differentiation from mesenchymal stem cells (MSCs). Human MSCs were allowed to differentiate into osteoblasts in culture. Concentrated hydrochloric acid was added to the medium to lower the bicarbonate concentration and pH. The expression of various osteoblastic genes and proteins and bone matrix mineralization were examined. Chronic metabolic acidosis enhanced the messenger RNA (mRNA) and protein expression of early osteoblast transcription factor, runx-2, whereas inhibiting osterix and having no effect on ATF-4. The expression of type I collagen, the most abundant bone matrix protein, was increased following the same pattern of runx-2. Likewise, metabolic acidosis slightly enhanced the expression of mature osteoblastic gene, osteocalcin. Study on mineralization revealed suppressed alkaline phosphatase mRNA and enzyme activity. Despite the augmented collagen deposit in acidic culture, bone matrix mineralization was impaired. In conclusion, chronic metabolic acidosis alters osteoblast differentiation from MSCs through its diverse effect on osteoblastic genes and proteins resulting in an impairment of bone formation.
远端肾小管酸中毒患者的骨组织学显示骨形成减少，骨基质矿化受损，而矿物质平衡的改变并不能完全解释这种情况。体外研究数据表明，代谢性酸中毒对成骨细胞功能有直接抑制作用。我们研究了慢性代谢性酸中毒对间充质干细胞（MSC）向成骨细胞分化的影响。在培养过程中，使人类MSC分化为成骨细胞。向培养基中加入浓盐酸以降低碳酸氢盐浓度和pH值。检测各种成骨细胞基因和蛋白质的表达以及骨基质矿化情况。慢性代谢性酸中毒增强了早期成骨细胞转录因子runx-2的信使核糖核酸（mRNA）和蛋白质表达，而抑制了osterix，对ATF-4没有影响。I型胶原蛋白是最丰富的骨基质蛋白，其表达也按照runx-2的相同模式增加。同样，代谢性酸中毒略微增强了成熟成骨细胞基因骨钙素的表达。矿化研究显示碱性磷酸酶mRNA和酶活性受到抑制。尽管酸性培养中胶原蛋白沉积增加，但骨基质矿化仍受损。总之，慢性代谢性酸中毒通过对成骨细胞基因和蛋白质的多种影响改变了MSC向成骨细胞的分化，导致骨形成受损。
