Disease relevance of Ank

• Spontaneous articular cartilage calcification, increased vertebral cortical bone formation, and peripheral joint and intervertebral ossific ankylosis are associated with both PC-1 deficiency and expression of truncated ANK in ank/ank mice [1].
• Progressive ankylosis, ank, a new recessive skeletal mutation causing a noninflammatory joint disease in mice is described [2].
• To determine its similarity to human spondylarthropathies, we studied murine progressive ankylosis, a spontaneously occurring disorder of joints in mice [3].
• INTRODUCTION: We have shown previously that the genetic ablation of tissue-nonspecific alkaline phosphatase (TNALP) function leads to amelioration of soft-tissue ossification in mouse models of osteoarthritis and ankylosis (i.e., Enpp1-/- and ank/ank mutant mice) [4].
• OBJECTIVE: To investigate whether HLA-B27 influences the expression of murine progressive ankylosis (MPA), a single-gene autosomal recessive mouse model of ankylosing spondylitis that arises in mice homozygous for the ank gene [5].

High impact information on Ank

• Here, we show that the ank locus encodes a multipass transmembrane protein (ANK) that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells [6].
• Craniometaphyseal dysplasia mutations do not transport pyrophosphate and cannot rescue the defects of Ank null mice [7].
• Furthermore, microcomputed tomography revealed previously unappreciated phenotypes in Ank null mice that are reminiscent of craniometaphyseal dysplasia [7].
• Chondrocalcinosis mutations retain apparently wild-type transport activity and can rescue the joint-fusion phenotype of Ank null mice [7].
• We also reconstruct two human mutations in a bacterial artificial chromosome and test them in transgenic mice for rescue of the Ank null phenotype and for induction of new skeletal phenotypes [7].

Chemical compound and disease context of Ank

• Progressive ankylosis mice (ank/ank) spontaneously develop a joint disorder characterized by calcium hydroxyapatite deposition and bony ankylosis of the joints of the axial and the appendicular skeleton [8].
• P5L mutation in Ank results in an increase in extracellular inorganic pyrophosphate during proliferation and nonmineralizing hypertrophy in stably transduced ATDC5 cells [9].
• Phosphocitrate prevents disease progression in murine progressive ankylosis [10].

Biological context of Ank

• RESULTS: Ank expression was detected at high levels at sites of both endochondral and intramembranous bone development [11].
• To this end, we examined the expression pattern of Ank mRNA during mouse embryonic development as well as in mouse hind limb joints with emphasis on the period when articular cartilage forms [11].
• Examination of ank mutant mice at earlier ages of tooth root formation indicated that this striking observation is apparent from the onset of cementogenesis [12].
• METHODS: Mice transgenic for HLA-B27 were bred with ank/ank mice, and the phenotypes of the F1 and F2 progeny were observed [5].
• CONCLUSION: HLA-B27 and the ank/ank genotype both predispose to diseases involving progressive bony ankylosis [5].

Anatomical context of Ank

• Wild-type osteoblasts treated with PP(i) showed an increase in OPN, and a decrease in Enpp1 and Ank expression [13].
• In situ hybridization and semi-quantitative RT-PCR were used to determine the effects of TGF-beta on Ank expression in metatarsal organ cultures [11].
• Treatment with TGF-beta resulted in an approximately four-fold induction of Ank mRNA in prehypertrophic chondrocytes and perichondrium of metatarsal cultures.CONCLUSIONS: The expression pattern of Ank suggests an important role both in inhibiting and regulating mineralization in the developing skeletal system [11].
• These initial studies using ank and PC-1 mutant mice were done to see if such mineral deposition and resulting ankylosis were occurring in the periodontium as well [12].
• Spondyloarthropathy in progressive ankylosis mice: ultrastructural features of the intervertebral disk [8].

Associations of Ank with chemical compounds

• Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders [13].
• The progressive ankylosis mutation provides a useful system for investigating calcium hydroxyapatite-associated arthropathies [14].
• No changes, however, occurred in the joint morphology of hydrocortisone-treated normal (ank/+) mice [15].
• Transient inhibition of murine progressive ankylosis by indomethacin [16].
• In the progressive ankylosis (ank) mouse, a premature termination mutation at glutamic acid 440 results in a phenotype characterized by inappropriate deposition of basic calcium phosphate crystals in skeletal tissues [9].

Regulatory relationships of Ank

• Upregulated ank expression in osteoarthritis can promote both chondrocyte MMP-13 expression and calcification via chondrocyte extracellular PPi excess [17].
• Since it was previously shown that TGF-beta regulates PPi transport in cells in culture, we also tested the hypothesis that TGF-beta regulates Ank expression [11].

Other interactions of Ank

• Developmental and TGF-beta-mediated regulation of Ank mRNA expression in cartilage and bone [11].

Analytical, diagnostic and therapeutic context of Ank

• METHODS: The localization of Ank mRNA was determined by radioactive in situ hybridization in E15.5 and E17.5 mouse embryos as well as in 1 and 3 week post-natal mice [11].
• Progressive ankylosis in mice. An animal model of spondylarthropathy. I. Clinical and radiographic findings [3].
• Murine progressive ankylosis was studied by light and electron microscopy (EM) [18].

References