Functional Roles of ANKH/Ank: Insights from CPPDD‐associated ANKH Mutations and the ank/ank Mouse

Review Article

Functional Roles of ANKH/Ank: Insights from CPPDD‐associated ANKH Mutations and the ank/ank Mouse

Florence WL Tsui^1,2, Facundo Las Heras^3,4, Robert D Inman^1–3 and Kenneth PH Pritzker^4,5
Affiliations: ¹Genetics and Development Division, Toronto Western Research Institute, Canada; ²Department of Immunology and ³Institute of Medical Science, University of Toronto, Canada; ⁴Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada and ⁵Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada


ABSTRACT

Calcium pyrophosphate dihydrate crystal deposition disease (CPPD arthropathy) is a common form of degenerative arthritis afflicting the elderly. Although the relationships between CPPD crystal arthropathy and osteoarthritis are controversial, it is clear that the mechanisms of CPPD crystal deposition and the mechanisms that promote cartilage matrix changes in osteoarthritis (OA) are different. Although considerable research attention has been paid to the basic mechanisms of OA, fewer studies have been conducted in CPPD; our understanding of the underlying disease processes remains woefully deficient. Rare genetic diseases with known gene mutations are extremely informative in unraveling the underlying disease mechanisms. Rare families with multiple CPPDD patients provide a good example in this respect. Earlier genetic studies on these families mapped the disease loci to chromosome 8q and 5p. Since the molecular cloning of ANKH (human homolog of progressive ankylosis; located on chromosome 5p), several dominant ANKH mutations that co‐segregate with disease were identified in a number of CPPDD families from different countries. This short review focuses on subsequent work addressing the functional consequences of these mutant ANKH proteins in an attempt to understand how these ANKH mutations might lead to CPPDD pathogenesis. Aside from gene mutations, spontaneous mouse mutants targeting the same gene provide complementary tools for unraveling the gene functions. Our recent finding in ank/ank mice showed that the ank defect results in articular chondrocyte hypertrophy (a novel observation) and increased calcified articular cartilage matrix, all preceding overt osteophyte formation and apatite crystal deposition, consequent to a single gene defect.

Keywords: progressive ankylosis, familial calcium pyrophosphate dihydrate crystal deposition disease, ANKH mutations, ank/ank mouse, tissue non‐specific alkaline phosphatase, sodium/phosphate co‐transporter PiT‐1, inorganic phosphate and pyrophosphate metabolism
Correspondence: F W L Tsui, Toronto Western Hospital, Mc14‐419, 399 Bathurst Street, Toronto, Ontario, M3T 2S8, Canada. Tel: (1)‐416‐603‐5904; Fax: (1)‐416‐603‐5745; e‐mail: ftsui@uhnres.utoronto.ca