Alcohol-Induced Adipogenesis in Bone and Marrow: A Possible Mechanism for Osteonecrosis

Abstract

The effect of alcohol on rabbit bone marrow and on the differentiation of mouse bone marrow stromal cells was investigated. Alcohol was administered intragastrically at a dose of 10 mL/kg/day for 1 to 6 months. Alcohol induced a significant increase in serum lipid peroxides, triglyceride, and cholesterol, and a reduction in superoxide dismutase activity. Fatty infiltration in the liver and adipogenesis in bone marrow were found histologically after alcohol administration. Fat cell hypertrophy and proliferation and diminished hematopoiesis in the subchondral area of the femoral head were observed. Triglycerides were deposited in osteocytes, which became pyknotic, and the percentage of empty osteocyte lacunae increased. None of these abnormal changes were detectable in the control group. In the in vitro study, the marrow stromal cells were treated with increasing (0.03, 0.09, and 0.15 mol/L) concentrations of ethanol for 4 to 21 days. Alcohol induced the differentiation of the cells into adipocytes. The number of adipocytes increased with longer durations of exposure to ethanol and with higher concentrations. Cells treated with ethanol also showed diminished alkaline phosphatase activity and expression of osteocalcin. These novel findings indicate that alcohol can directly induce adipogenesis, decrease osteogenesis in bone marrow stroma, and produce intracellular lipid deposits resulting in the death of osteocytes, which may be associated with the development of osteonecrosis, especially in patients with long-term and excessive use of alcohol.

Use of small interfering ribonucleic acids to inhibit the adipogenic effect of alcohol on human bone marrow-derived mesenchymal cells

“…Quantitative analysis of the mRNA levels by real-time RT-PCR method revealed that Osf2/Cbfa1, the marker gene for osteogenesis in the PPARγ-siRNA group, was up-regulated by 17.4% compared to the adipogenic control group (P= 0.000), and almost reached the gene level of cells cultured in pure osteogenic medium without alcohol (P=0.302).…”

“…Several's studies [15][16][17] have provided evidence that alcohol shifts lineage commitment and differentiation of MSCs from osteogenesis to adipogenesis by upregulation of gene expression for peroxisome proliferator-activated receptor gamma (PPARγ); however, the molecular mechanism underlying the reciprocal relationship is not yet well understood.…”

Osteogenic abilities of bone marrow stromal cells are not defective in patients with osteonecrosis

“…For alcohol-induced ONFH to develop in adults, the total alcohol exposure threshold needs to be approximately 150 L of 100% ethanol, which corresponds to a consumption of 400 mL or more of absolute ethanol per week [23]. We determined the weekly alcohol consumption by summing the ethanol contents of beverage types consumed over a typical week.…”

Osteonecrosis of the femoral head: diagnosis and classification systems

“…Studies have demonstrated that alcohol contributes to abnormal lipid metabolism in the stromal cells of bone marrow, decreasing osteogenesis while enhancing adipogenesis. This abnormal metabolism produces intracellular lipid deposits resulting in the death of osteocytes, which may be associated with the development of ON [12]. The adipogenesis may also pack the marrow, thereby increasing the intraosseous pressure and negatively affecting the bone microcirculation.…”