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.