Wilma and Roswell Messing Professor of Pathology and Immunology
Our laboratory focuses on the mechanisms by which osteoclasts resorb bone. Our general strategy is to establish that deletion of a molecule of interest, in vivo, produces a robust skeletal phenotype. If we find such is the case, we employ molecular and cellular techniques to determine the mechanisms by which the targeted molecule regulates the osteoclast and potential clinical relevance. We have established that organization of the osteoclast’s unique cytoskeleton, which is central to its capacity to resorb bone, is mediated by an αvβ3 integrin-activated signaling complex involving c-Src, Syk, Dap12, Slp76, Vav3 and Rac. We have proven the physiological relevance of each of these signaling molecules as their deletion results in osteoclast dysfunction and osteopetrosis, in vivo. Deletion of these molecules is also protective of pathological bone loss and thus, they are candidate therapeutic targets. We have established that the osteoclastogenic cytokines, M-CSF and RANK ligand, regulate the osteoclast cytoskeleton by stimulating the same signals as the αvβ3 integrin. In the case of M-CSF, its collaboration with the integrin represents inside-out conformational stimulation mediated by talin. RANK ligand, on the other hand, requires αvβ3 for its cytoskeletal effects, but by different mechanisms which are presently under investigation. Finally, we have established that the osteoclast exerts its bone resorptive effects by functioning as a secretory cell wherein lysosomal vesicles containing skeleton-degrading molecules polarize and insert into the bone-apposed plasma membrane under the influence of Synaptotagmin VII and autophagy proteins. The polarized resorptive machinery thereby creates an isolated extracellular microenvironment in which bone is degraded.
- MD: 1964, Washington University, St. Louis
- Pathology & Immunology
- Molecular Cell Biology
- Diabetes Research Center
- Division of Bone and Mineral Diseases
Our laboratory has been exploring mechanisms of preventing obesity and have discovered that genetic modulation of myeloid lineage cells to a novel hypoinflammatory phenotype completely prevents high fat diet induced weight gain (J Clin Invest. 2020;130(5):2644-2656 Because obesity is a risk factor for Alzheimer’s disease we are determining if its prevention by this strategy will reduce dementia development in mice. We are particularly focused on microglia, which are myeloid lineage cells and assume an activated state in response to high fat diet.