Multiscale Evaluation of the Skeletal Response to Perturbed pH Homeostasis

Metabolic acidosis (MA) is clinically characterized by a decrease in blood pH and bicarbonate (HCO3-). To reestablish pH homeostasis in MA, bone dissolution acts as a source of buffering alkali. This aids in systemic pH balance; however, it also leads to bone loss and functional limitations for skeletal tissue, increasing the incidences of osteodystrophy, osteopenia, and osteoporosis. The basis of the cellular response to MA driving bone loss remains largely unknown, therefore preventing effective treatment of this deleterious response. As such, current clinical therapeutics for MA utilize administration of alkaline substrates to buffer excess protons in order to raise pH. However, there is no general consensus on treatment clinically. Osteoclasts are bone-resorbing cells which are stimulated by acidity, and are believed to be the primary cells contributing to MA-induced bone loss. Osteoclast resorption serves to release alkaline ions from the bone to buffer the acidic environment, concomitantly furthering bone loss. Here, I aimed to elucidate the biological mechanisms behind acidosis-induced bone deterioration. By characterizing in vivo and in vitro metabolic acidosis models, I demonstrate that the relationship between osteoclasts and acidosis is nonlinear, as should be anticipated of most biological phenomena. Instead, it appears the stage of osteoclast maturity upon exposure to acidity regulates the resorption response. Ultimately, we established an in vivo model of MA in mice, and demonstrated acidosis-induced bone loss is dependent on quantity of acid-loading, duration of acidosis, and may result from altered hematopoiesis dynamics in MA.