University of Toronto Biochemistry

	Morris F. Manolson Associate Professor Ph.D., McGill, 1988
	Faculty of Dentistry, 124 Edward Street Room 403 416-979-4900 #4392 m.manolson@utoronto.ca

Assembly, Targeting, and Control of Proton Pumping V-ATPases

Research Synopsis

Inflammatory arthritis not only causes painful swelling of affected joints, but also results in the loss of bone material around the arthritic joints. The pathological bone loss associated with arthritis results in increased bone fractures, deformation and collapse of joint surfaces, and difficulties in replacing the arthritic joints with implants and prostheses. We now know that the cells responsible for this bone loss (osteoclasts) resorb bone by pumping acid directly onto the bone surface; the secreted acid literally dissolving the bone surface away. In healthy bone, a percentage of the skeleton is continually dissolved away and remade (~15% of an adult's skeleton/year) in order to repair micro-fractures in the bone that occur
daily with every moderate bump to one's skeleton. In inflammatory arthritis, this normal process of bone resorption becomes pathologically accelerated and results in an overall loss of bone around the arthritic joints.

My past work has been to advance our understanding of exactly how the osteoclast acid pumps (V-ATPases) pump the acid onto the bone. With my
knowledge of the osteoclast acid pump, I am now focused on trying to develop
therapeutic reagents that will specifically stop the acid pumps in order to prevent the accelerated bone loss associated with inflammatory types of arthritis, such as rheumatoid arthritis, psoriatic arthritis, reactive arthritis, juvenile rheumatoid arthritis and lupus.

Selected Publications

G ramoun A., Shorey S., Bashutski J.D., Dixon S. J., Sims S. M. , Heersche J. N. M., Manolson M. F. The effects of Vitaxin, a novel therapeutic in trial for metastatic bone tumors, on osteoclast functions in vitro. Accepted by the Journal of Cellular Biochemistry, January 2007. Manuscript #JCB-06-0707.

Chong, S.A.C. , Lee, W., Arora, P.D., Laschinger, C. , Young, E.W.K., Simmons, C.A., Manolson, M.F. , Sodek, J., McCulloch, C.A.. Methylglyoxal Inhibits the Binding Step of Collagen Phagocytosis . J Biol Chem. 2007 Mar 16;282(11):8510-20.

Trebec, D., Keying, L. , Chandra, D., Gramoun, A., Heersche, J.N.M. and Manolson, M.F. Differential expression of activation factors in large and small osteoclasts. J Cell Biochem. 2007 May 1;101(1):205-20.

Ochotny, N., Van Vliet, A., Chan, N., Yao, Y. von Schroeder, H.P., Heersche, J.N.M. and Manolson, M.F., Effects of Human a3 and a4 Mutations that Result in Osteopetrosis and Distal Renal Tubular Acidosis on Yeast V-ATPase Expression and Activity. J. Biol. Chem. 281:26102-26111, 2006.

Ochtny N.M., Van Vliet A., Chan N., Yao Y., Morel M., Kartner N., von Schroeder H.P., Heersche J.N., and Manolson M.F. Effects of human a3 and a4 mutations that result in osteopetrosis and distal renal tubular acidosis on yeast V-ATPase expression and activity. J. Biol. Chem. Jul 13, 2006. [Epub ahead of print]

Voronov I., Heersche J.N., Casper R.F., Tenenbaum H.C., and Manolson M.F. Inhibition of osteoclast differentiation by polycyclic aryl hydrocarbons is dependent on cell density and RANKL concentration. Biochem Pharmacol. 70: 300-307, July 2005.

Shorey S., Heersche J.N.M., Manolson M.F. Differences in the degree to which osteoclasts from different parts of the skeleton employ cysteine proteinases and matrix metalloproteinases. Accepted in Bone, June 2004.

Manolson, M.F., Yu, H., Chen, W., Yao, Y., Li, K., Lees, R., and Heersche, J.N.M. The a3 isoform of the 100 kDa V-ATPase subunit is highly but differentially expressed in large (>310 nuclei) and small (<5 nuclei) osteoclasts. J. Biol. Chem. 278: 49271-49278, 2003.

Landolt-Marticorena, C., Williams, K., Correa, J., Chen, W. and Manolson, M.F. Evidence that the V-ATPase Vo subunit, Vphlp, interacts directly with
the Vmal3p and Vmalp subunits of the V1 sector. J. Biol. Chem. 275:
15449-15457, 2000.

Landolt-Marticorena, C., Kahr, W.H., Zawarynski, P., Correa, J., and Manolson, M.F. Substrate- and inhibitor-induced conformational changes in the yeast V-ATPase provide evidence for communication between the catalytic and proton-translocating sectors. J. Biol. Chem. 274:26057-26064, 1999.

Plant, P.J., Manolson, M.F., Grinstein, S. and Demaurex, N. Alternative
mechanisms of vacuolar acidification in vacuolar H+-ATPase deficient yeast.J. Biol. Chem., 274: 37270- 37279, 1999.

Leng, X.-H., Manolson, M.F., and Forgac M.Function of the C-terminal domain of Vph1p in activity and assembly of the yeast V-ATPase. J. Biol. Chem. 273:6717-6723, 1998.

Leng, X.-H., Manolson, M.F.. Liu, Q. and Forgac M. Site-directed mutagenesis of the 100 kDa subunit (Vph1p) of the yeast vacuolar (H+)-ATPase. J. Biol. Chem. 271:22487-22493, 1996.

Manolson, M.F., Wu, B., Proteau, D., Taillon, B.E., Roberts, B.T., Hoyt, M.A. and Jones, E.W. The STV1 gene encodes a functional homologue of the 95 kDa yeast vacuolar H+-ATPase subunit, Vphlp. J. Biol. Chem. 269:14064-14074, 1994.

Manolson, M.F., Proteau, D., Preston, R.A., Stenbit, A., Roberts, B.T., Hoyt, M.A., Preuss, D., Mulholland, J., Botstein, D. and Jones, E.W. The VPH1 gene encodes a 95 kDa integral membrane polypeptide required for in vivo assembly and activity of the yeast vacuolar H+-ATPase. J. Biol. Chem. 267:14294-14303, 1992.

Manolson, M.F., Ouellette, B.F.F., Filion, M. and Poole, R.J. cDNA sequence and homologies of the "57 kDa" nucleotide-binding subunit of the vacuolar ATPase from Arabidopsis. J. Biol. Chem. 263:17987-17994, 1988.

Manolson, M.F., Rea, P.A. and Poole, R.J. Identification of 3-0-(4-benzoyl)benzoyladenosine 5'-triphosphate- and n,n,'-dicyclohexyl-carbodiimide-binding subunits of a higher plant H+-translocating ATPase. J. Biol. Chem. 260:12273-12279, 1985.

Last Modified: 16 August 2007, 09:57 AM