Cooper Medical School of Rowan University
Department of Biomedical Sciences
401 South Broadway, Suite 356
Camden, NJ 08103
Rutgers University, New Brunswick, NJ
Osteoarthritis, chondrocalcinosis, pathological calcification, geneticsof rheumatic diseases
We discovered a gene,termed ANK (progressive ankylosis), whose mutations result in the pathologicaldeposition of calcium pyrophosphate crystals in joints. ANK is a multipasstransmembrane protein that is ubiquitously expressed, and that has no homologyto any other protein except its orthologs. ANK apparently acts as a transporterfor inorganic pyrophosphate (PPi) from intracellular metabolic reactions to theextracellular space where it, most importantly, inhibits inappropriatehydroxyapatite mineralization. However, too much extracellular PPi, under theappropriate conditions, can give rise to calcium pyrophosphate crystaldeposition. Besides structural studies of ANK, we are exploring the possibilitythat ANK acts as an ATP efflux effector in certain cell types. Although ouroriginal interest in ANK was in cartilage tissue, ANK is also expressed in thebrain, and mutations at the N-terminus of the protein are known to result infebrile seizures.
Zaka R, Stokes D, Dion AS,Kusnierz A, Han F, Williams CJ. P5L mutation in Ank results in an increase inextracellular PPi during proliferation and non-mineralizing hypertrophy instably tansduced ATDC5 cells. Arthritis Res. Ther., 8(6):R164, 2006.
Zaka R, Dion AS, Kusnierz A,Bohensky J, Srinivas V, Freeman T, Williams CJ. Oxygen tension regulates theexpression of ANK in a HIF-1 dependent manner in the growth plate. J BoneMin Res 2009 Nov;24(11):1869-78.
Oca P, Zaka R, Dion AS, WilliamsCJ. Pi and Ca++ influx arerequired for TGFβ-mediated stimulation of ANK expression and function duringchondrogenesis. J Cell Physiol 2010; 224:540-548.
Skubutyte R, Markova D, FreemanTA, Dion AS, Anderson DG, Williams CJ, Shapiro IM, Risbud M. HIF regulation ofANK expression in nucleus pulposus cells: A cellular strategy to preventdystrophic mineralization in the intervertebral disc? Arthritis Rheumatism2010; 69:2707-2715.
Roman-Blas J, Dion AS,Seghatoleslami MR, Guinta K, Oca P, Jimenez SA, Williams CJ. Expression of MEDand PSACH COMP mutations affect chondrogenesis in chicken limb bud micromasscultures. J Cell Physiol 2010; 224:817-826.
Williams CJ. Genetics andClinical Applications. In: Addressing Unmet Needs in Osteoarthritis.Martel-Pelletier J and Pelletier J-P, eds. Chapter 3, pp. 38-53, FutureMedicine Pubs., London, March, 2013.
Dion AS, Zaka R and Williams CJ.A testable topological protein model for ANK: An inorganic pyrophosphatetransporter. FEBS J, in revision.