Cellular and molecular mechanisms of alcohol-induced osteopenia

Abstract

Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs.

Keywords: Alcohol; Bone formation; Bone resorption; Mechanisms; Osteopenia; Pathophysiology.

Fig. 1

Schematic diagram of direct and indirect mechanisms effect on alcohol and its metabolism acetaldehyde (Acet) induced signaling cascades in osteopenia. In osteoblasts, decreased estradiol expression followed by phosphorylation of ERK/STAT3 cascades leads to increased RANKL level, and then binds to RANK to further decrease bone formation. Expression level of ROS is mainly induced by NOX enzyme family, NOX 1, 2, 4. Moreover, increased NOX activity depends on NF-κB, JNK, ERK signaling pathways to stimulate RANKL expression. Increased level of proinflammatory cytokine IL-6 may mediate the signal transportation through a protein kinase C-dependent pathway to increase RANKL expression. Inhibited PTH–vitamin D axis can be partly mediated by Wnt pathway with heavy alcohol consumption, which in turn promotes RANKL expression in osteoblasts. Decreased GH production and IGF-1 expression were found in osteoblasts, accompanied by increased IGF binding protein IGFBP1, with followed downstream signaling pathway mTOR/S6K1 to reversely inhibit Runx2 mRNA expression. NOX NADPH oxidase, ROS reactive oxygen species, PKC protein kinase C, PTH parathyroid hormone, GH growth hormone, IGF insulin-like growth factor, RANKL receptor activator of nuclear factor kappa-B ligand

Fig. 2

Direct and indirect mechanisms effect on ethanol (ETOH)-induced osteoclast activation and osteoclastogenesis via RANKL/RANK signaling cascades in osteopenia. Other inflammatory cytokines, including TNF-α and IL-6, also have directly positive effect on osteoclasts. However, their downstream signaling cascades remain unsolved and need further research. RANK receptor activator of nuclear factor kappa-B, RANKL RANK ligand, SOST sclerostin

Fig. 3

Schematic diagram of direct and indirect mechanisms effect on ethanol induced signaling cascades in osteopenia by bone marrow mesenchymal stem cells (BMMSCs). Ethanol treatment has direct effect on BMMSCs by ROS accumulation and Wnt inhibition, which in turn support a shift in BMMSCs differentiation towards adipocyte lineage over the osteoblast lineage. In addition, ethanol also increases TNF-α production in BMMSCs with ROS activation. Heavy alcohol consumption activates PI3K/AKT/mTOR signaling cascades in BMMSCs by inhibiting osteogenic differentiation and promoting adipogenic differentiation, with increased PPAR-γ production and inhibited Runx2 mRNA expression