Reduced bone formation in alcohol-induced osteopenia is associated with elevated p21 expression in bone marrow cells in aldehyde dehydrogenase 2-disrupted mice

IntroductionHigh consumption of alcohol is one of the risk factors for osteoporosis. Approximately 45% of Chinese and Japanese individuals have the inactive aldehyde dehydrogenase 2 (Aldh2) phenotype. The absence of the ALDH2*2 allele is found to adversely influence the risk of osteoporosis. The aim of this study is to clarify the effects of alcohol consumption on osteoblast differentiation in bone marrow and trabecular bone formation in Aldh2-disrupted mice.Materials and methodsSeven-week-old male Aldh2 knockout mice (Aldh2−/−) and wild-type (Aldh2+/+) mice were fed with water (groups Aldh2−/−/Wa and Aldh2+/+/Wa) or with 5% ethanol (groups Aldh2−/−/Al and Aldh2+/+/Al) for 4 weeks. At the age of 12 weeks, bone histomorphometry was performed at the secondary spongiosa of the tibias. Bone marrow cells from the bilateral femurs and tibias were used for mRNA expression analysis.ResultsHistomorphometrical study revealed that trabecular bone was significantly reduced in the Aldh2−/−/Al group compared with that in the Aldh2−/−/Wa and Aldh2+/+/Wa groups. Bone formation rate was significantly decreased in Aldh2−/−/Al compared with the other three groups. Quantitative RT-PCR revealed a significant decrease in type I collagen, osterix, osteopontin, and osteocalcin mRNA expressions in Aldh2−/−/Al compared with Aldh2−/−/Wa. In bone marrow cell cultures, mineralized nodule formation in Aldh2−/−/Al was significantly decreased compared with that in Aldh2+/+/Wa and Aldh2−/−/Wa, while PAK18, a p21-activated kinase inhibitor, recovered the decreased mineralized nodule formation in Aldh2−/−/Al.ConclusionAlcohol consumption suppressed the differentiation and mineralization of osteoblasts and then reduced trabecular bone formation and bone volume in association with the elevated p21 expression in bone marrow cells, especially in aldehyde dehydrogenase 2-disrupted mice.

Research Highlights
► Trabecular bone and bone formation rate by histomorphomerical study and osteocalcin mRNA expressions by quantitative RT-PCR were significantly decreased in Aldh2−/−/Al compared with other groups.
► Mineralized nodule formation in Aldh2−/−/Al was significantly decreased compared with that in Aldh2−/−/Wa, while PAK18 (p21-activated kinase inhibitor) recovered the decreased mineralized nodule formation in Aldh2−/−/Al.
► Alcohol consumption suppressed the differentiation and mineralization of osteoblasts and then reduced trabecular bone formation and bone volume in association with the elevated p21 expression in bone marrow cells, especially in Aldh2−/− mice.