The role of osteocytes in alcohol-induced osteopenia

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Numerous epidemiological studies support that heavy alcohol consumption is linked to lower bone mineral density (BMD), a significant risk factor for the development of osteoporosis. Early life alcohol use is particularly undermining to bone health in adulthood as the result of impaired attainment of peak bone mass, a concerning finding considering the increasing rate of alcohol consumption in adolescents. Confounding the problem, ethanol also compromises bone’s mechanical properties, which decreases bone quality and increases fracture risk, even in the absence of decreased bone mass. Clinically, measurements of bone quality aren’t implemented, nor is this aspect routinely considered in bone disease management. The literature strongly suggests that osteocytes play a pivotal role in maintaining bone quality, yet the effects of alcohol on these cells and their processes are poorly understood. Osteocytes have been recently appreciated to actively deposit and resorb bone in their microenvironment, a process called perilacunar/canalicular remodeling (PLR). PLR mediators ensure proper collagen organization and bone mineralization. Further, osteocytes are pivotal in bone homeostasis through their release of cell specific proteins, such as sclerostin. This protein is of particular interest as it inhibits a pro- osteoblastic pathway (Wnt signaling) that is known to be inhibited by ethanol. Importantly, sclerostin also modulates PLR, specifically promoting acidification to allow for perilacunar resorption (osteocytic osteolysis). Finally, both PLR and sclerostin production are regulated by TGF-ß signaling, an important bone anabolic pathway known to be dysregulated in musculoskeletal diseases marked by decreased quality. The studies proposed in this application are designed to uncover how, mechanistically, alcohol affects osteocytes, and the extent to which these effects prevail in a complex physiological system. The overall hypothesis is that ethanol increases TGF-ß signaling in osteocytes, which promotes sclerostin release and disrupts PLR, resulting in fragile bone. Specific Aim 1 will use in vitro and in vivo studies to assess how ethanol alters PLR and the osteocyte microenvironment, and whether these changes significantly increase fracture risk. Specific Aim 2 will analyze serum samples from a human clinical cohort and a rhesus macaque study to see whether ethanol consumption results in increased serum sclerostin, which could act as a useful biomarker for PLR status. Specific Aim 3 investigates a mechanistic pathway uniting these two phenomena and uses again in vitro and in vivo studies to determine if TGF-ß signaling is at the core of the observed changes. Altogether, these studies will generate new mechanistic insights into the role of osteocytes in alcohol-induced osteopenia and allow to narrow the clinical gap that exists in treating quality-driven musculoskeletal conditions.