Bone loss is a common clinical manifestation in many diseases, including osteoporosis, inflammatory arthritis, and cancer related osteolysis. The ultimate goal of our group is to understand the molecular mechanisms that lead to pathological bone loss and to develop therapeutics to prevent it.
Bone is a highly dynamic tissue in which bone matrix production and mineralization and bone resorption occurs continuously throughout life. This process, collectively termed remodeling, is performed by two bone cell types: the osteoblast (the “bone forming” cell) and the osteoclast (the “bone resorbing” cell). To resorb bone, osteoclasts pump acid onto the surface; this is necessary to demineralize bone and to create favorable conditions for the tissue enzymes to digest the extracellular matrix. This acidification is achieved by the vacuolar H+-ATPases (V-ATPases), proton translocating enzymes highly enriched in osteoclasts. V-ATPases are multisubunit proton pumps and they consist of at least 14 subunits organized into cytosolic (V1) and transmembrane (V0) domains.
Of a particular interest to our group is the biology and function of the V-ATPase “a” subunit, the subunit that is, in part, responsible for proton translocation. We have three main research streams:
(1) Elucidating the structure and function of the V-ATPase “a” subunit, including its topology, post-secondary modifications, and interaction with the other V-ATPase subunits
(2) Understanding the role of V-ATPases and in vesicular acidification in osteoclast differentiation, function and signal transduction.
(3) Developing V-ATPase inhibitors as potential therapeutics to prevent bone loss