Research in my laboratory primarily focuses on the genetic regulation of tissue mineralization. Bones and teeth are the tissues where physiologic mineral depositions take place. These mineralized tissues serve important biomechanical functions and also act as a reservoir for essential mineral ions required in vital cellular activities. Soft tissue mineralization, on the other hand, is pathologic, which often leads to debilitating conditions. Mineral deposition in the arterial walls can be a risk factor for many cardiovascular diseases, while such deposits in the joints can cause osteoarthritis - a common chronic joint condition of the elderly in Canada. Our working hypothesis suggests that mineral deposition in a tissue depends on the availability of two key mineral ions calcium and inorganic phosphate, the presence of a suitable mineral scaffolding protein matrix and the extracellular levels of inhibitors that prevent mineral crystal precipitation and growth. We use the power of modern mouse genetics in combination with a range of molecular and cell biology techniques to uncover the novel genetic regulators of tissue mineralization and their mechanisms of action. Revealing these regulators should eventually help identify new therapeutic targets and improve the management of complications associated with abnormal tissue mineralization.
- Transgenic models
- Bone remodelling
- Bone mineralization
- Arterial calcification
Hussein O, Tiedemann K, Murshed M and Komarova SV. Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases. Cancer Lett. 2012 Jan 28;314(2):176-84. Epub 2011 Sep 29.
Khavandgar Z, Poirier C, Clarke CJ, Li J, Wang N, McKee MD, Hannun YA and Murshed M. A Cell-Autonomous Requirement for Neutral Sphingomyelinase 2 in Bone Mineralization. J Cell Biol. 2011 Jul 25; 194(2):277-89.
Li JJ, Khavandgar Z, Lin SH and Murshed M. Lithium chloride attenuates BMP-2 signaling and inhibits osteogenic differentiation through a novel WNT/GSK3- independent mechanism. Bone. 2011 Feb 1;48(2):321-31.
Murshed M and McKee MD. Molecular determinants of extracellular matrix mineralization in bone and blood vessels. Curr Opin Nephrol Hypertens. 2010 Jul;19(4):359-65.
Lee YC, Huang CF, Murshed M, Chu K, Araujo JC, Ye X,deCrombrugghe B,Yu-Lee LY, Gallick GE and Lin SH. Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts. Oncogene. 2010 Jun 3;29(22):3196-207.
Shi Y, Oury F, Yadav VK, Wess Y, Liu XS, Guo XE, Murshed M and Karsenty G. Signaling through the M3 muscarinic receptor favors bone mass accrual by decreasing the sympathetic activity. Cell Metab. 2010 Mar 3;11(3):231-8.
Kaipatur NR, Murshed M and McKee MD. Protein inhibition of tooth mineralization in vivo: Ectopic expression of matrix Gla protein in the dentin and periodontium of Col1a1-Mgp transgenic mice. J Dent Res. 2008 Sep;87(9):839-44.
Kaartinen MT, Murshed M, Karsenty G, McKee MD. Osteopontin Upregulation and Polymerization by Transglutaminase 2 in Calcified Arteries of Matrix Gla Protein-deficient Mice. J Histochem Cytochem. 2007 Apr;55(4):375-86.
Zaheer A, Murshed M, Karsenty, G. Optical imaging of Hydroxyapatite in the calcified vasculature of transgenic animals. Arterioscler Thromb Vasc Biol. 2006 May;26(5):1132-6.
Murshed M, Harmey D, Millan JL, McKee MD, Karsenty G. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev. 2005 May 1;19(9):1093-104.
Bader B L, Smyth N, Nedbal S, Miosge N, Baranowsky A, Mokkapati S, Murshed M, and Nischt R.Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice. Mol Cell Biol. 2005 Aug;25(15):6846-56.
Murshed M, Schinke T, McKee MD, Karsenty G. Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J Cell Biol. 2004 Jun 7;165(5):625- 30.
McKee MD, Kaipatur N, Giachelli CM, Murshed M and Karsenty G. Regulation of biomineralization: Lessons learned from bone and cartilage, and from pathologic calcification. Proc. 8th Intl. Conf. Chem. Biol. Mineralized Tissues, eds. WJ Landis and J Sodek. Pub. By ICCBMT, Toronto. 2004 pp. 95-98.
El-Maadawy S, Kaartinen MT, Schinke T, Murshed M, Karsenty G, McKee MD.Cartilage formation and calcification in arteries of mice lacking matrix Gla protein. Connect Tissue Res. 2003; 44 Suppl 1:272-8.
Murshed M, Smyth N, Miosge N, Karolat J, Krieg T, Paulsson M, Nischt R. The absence of nidogen 1 does not affect murine basement membrane formation. Mol Cell Biol. 2000 Sep;20(18):7007-12.
Murshed M and Karsenty G. Genetic analysis of skeleton physiology. Endocrinology, Fifth edition, 2005. Edited by Jameson J. L. and DeGroot L. J., published by Elsevier Inc.
Extracellular matrix and mineralization of craniofacial bone. McKee M, Murshed M and Kaartinen M. Mineralized Tissues in Oral and Craniofacial Science: Biological Principles and Clinical Correlates.