Chronic metabolic acidosis alters osteoblast differentiation from human mesenchymal stem cells.
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.
Disthabanchong
S
S
Division of Nephrology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. sineemd@hotmail.com
Radinahamed
P
P
Stitchantrakul
W
W
Hongeng
S
S
Rajatanavin
R
R
D000141:Acidosis, Renal Tubular / Q000235:genetics / Q000378:metabolism*; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D001857:Bone Matrix / Q000378:metabolism; D002113:Calcification, Physiologic / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002908:Chronic Disease; D024042:Collagen Type I / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C497109:ATF4 protein, human; D024042:Collagen Type I; D050659:Core Binding Factor Alpha 1 Subunit; D012333:RNA, Messenger; C493709:RUNX2 protein, human; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; D014157:Transcription Factors; D051701:Activating Transcription Factor 4