Irina Voronov, Ph.D.
Dental Research Institute
Faculty of Dentistry, University of Toronto
Faculty of Dentistry
124 Edward Street, rm 430
Toronto, Ontario, Canada
Office: 416-979-4900 ext.1-4530
Lab: 416-979-4900 ext. 1-4573
Source of Funding: The Arthritis Society
Operating grant title: “Role of the V-ATPases in osteoclast signal transduction”
Funding period: 07/2012 – 06/2015
The objective of my research program is to elucidate roles of vacuolar H+-ATPases (V-ATPases) and lysosomal pH in osteoclast signaling. To study osteoclast signaling, we use a mouse model with a point mutation (R740S) in the V-ATPase a3 subunit, a protein highly expressed in these cells. Our results show that osteoclasts derived from the heterozygous mice (+/R740S) have higher lysosomal pH, decreased osteoclastogenesis in vitro, and impaired activation of nuclear factor of activated T cells (NFATc1), the key transcription factor, indicating that lysosomal pH plays a role in osteoclast signaling.
Osteoclasts are the cells implicated in bone destruction associated with rheumatoid arthritis, osteoporosis and cancer-related bone lysis, therefore, these findings have far reaching clinical implications. For example, medications, such as the antimalarial lysosomotropic drug chloroquine, are used for treatment of rheumatic diseases; however, the precise mechanism of how chloroquine alleviates the symptoms in rheumatoid arthritis is not known. It has been already shown that chloroquine raises the pH of acidic compartments, affecting receptor recycling, protein processing, and production of cytokines, such asTNF-α, IL-1β and IL-6. We demonstrated that changes in lysosomal pH also affect transcription factor signaling in osteoclasts, providing additional information regarding the potential molecular mechanisms of chloroquine action.