Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL)

Nakamura, Isao; Ikegawa, Shiro; Okawa, Akihiko; Okuda, Shujiro; Koshizuka, Yu; Kawaguchi, Hiroshi; Nakamura, Kozo; Koyama, Tsunemaro; Goto, Sumio; Toguchida, Junya; Matsushita, Masafumi; Ochi, Takahiro; Takaoka, Kunio; Nakamura, Yusuke

doi:10.1007/s004390050993

Cited by 167 publications

(117 citation statements)

References 19 publications

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“…Interestingly, these genes included Dmp1, Ank, and Enpp1, all of which are known to play key roles in the process of extracellular matrix mineralization not only in mice but also in humans. (35)(36)(37)(38)(39)(40)(41)(42)(43) Moreover, since we observed that, at least relative to Alpl, all three genes were expressed at lower levels in Mdk-deficient osteoblasts, it is reasonable to speculate that these results provide a molecular explanation for the skeletal phenotype of Mdk-deficient mice. As discussed below, this is particularly true for Ank and Enpp1, whereas the decreased expression of Dmp1 rather should result in other abnormalities.…”

Section: Discussionmentioning

confidence: 72%

“…playing a role in the regulation of extracellular matrix mineralization in mice and humans. (36)(37)(38)(39)(40)(41)(42)(43) In contrast, Mdk did not affect the expression of other osteoblast marker genes, such as Ibsp (encoding bone sialoprotein), Alpl (encoding tissuenonspecific alkaline phosphatase), and Bglap (encoding osteocalcin). To confirm these data, we next performed quantitative RT-PCR using independently isolated cultures and found a significant induction of Dmp1, Ank, and Enpp1 expression following Mdk administration, whereas expression of Alpl was reduced significantly (Fig.…”

Section: Increased Cortical Bone Resorption In Aged Mdk-deficient Micementioning

confidence: 93%

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Increased trabecular bone formation in mice lacking the growth factor midkine

Neunaber

Catalá-Lehnen

Beil

et al. 2010

Journal of Bone and Mineral Research

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Midkine (Mdk) and pleiotrophin (Ptn) comprise a family of heparin-binding growth factors known primarily for their effects on neuronal cells. Since transgenic mice overexpressing Ptn have been reported to display increased bone density, we have previously analyzed Ptndeficient mice but failed to detect any abnormality of skeletal development and remodeling. Together with the finding that Mdk expression increases in the course of primary osteoblast differentiation, we reasoned that Mdk, rather than Ptn, could play a physiologic role in bone formation. Here, we show that Mdk-deficient mice display an increased trabecular bone volume at 12 and 18 months of age, accompanied by cortical porosity. Histomorphometric quantification demonstrated an increased bone-formation rate compared with wild-type littermates, whereas bone resorption was differentially affected in trabecular and cortical bone of Mdk-deficient mice. To understand the effect of Mdk on bone formation at the molecular level, we performed a genome-wide expression analysis of primary osteoblasts and identified Ank and Enpp1 as Mdk-induced genes whose decreased expression in Mdk-deficient osteoblasts may explain, at least in part, the observed skeletal phenotype. Finally, we performed ovariectomy and observed bone loss only in wild-type but not in Mdk-deficient animals. Taken together, our data demonstrate that Mdk deficiency, at least in mice, results in an increased trabecular bone formation, thereby raising the possibility that Mdk-specific antagonists might prove beneficial in osteoporosis therapy. ß

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Section: Discussionmentioning

confidence: 72%

Section: Increased Cortical Bone Resorption In Aged Mdk-deficient Micementioning

confidence: 93%

Increased trabecular bone formation in mice lacking the growth factor midkine

Neunaber

Catalá-Lehnen

Beil

et al. 2010

Journal of Bone and Mineral Research

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“…OPLL is a common disorder in Asia, particularly in Japan, where the incidence is 1.5% among people over 50 years of age. Polymorphisms of the PC-1 gene, of currently unknown functional significance, have been reported in Japanese subjects with OPLL (40,41). The PC-1 KO mice are also an accepted animal model for diffuse idiopathic skeletal hyperostosis and ankylosing spinal hyperostosis (refs.…”

Section: Discussionmentioning

confidence: 99%

Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization

Hessle

Johnson

Anderson

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

779

629

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I n the process of bone formation, osteoblasts mineralize the matrix by promoting the seeding of basic calcium phosphate crystals of hydroxyapatite in the sheltered interior of shed membrane-limited matrix vesicles (MVs) and by propagating hydroxyapatite mineral onto the collagenous extracellular matrix (osteoid; refs. 1 and 2). Tissue-nonspecific alkaline phosphatase (TNAP), an isozyme of a family of four homologous human alkaline phosphatase genes (3), plays a role in bone matrix mineralization. Deactivating mutations in the TNAP gene causes the inborn error of metabolism known as hypophosphatasia (4), characterized by poorly mineralized cartilage (rickets) and bones (osteomalacia), spontaneous bone fractures, and elevated extracellular inorganic pyrophosphate (PP i ) concentrations (5). The severity and expressivity of hypophosphatasia depends on the nature of the TNAP mutation (6). TNAP is present in MVs (7), and it has been proposed that the inorganic phosphate (P i )-generating activity of TNAP is required to generate the P i needed for hydroxyapatite crystallization (8-10). However, the ability of TNAP to hydrolyze PP i also has been hypothesized to be important to promote osteoblastic mineralization (11, 12), because PP i suppresses the formation and growth of hydroxyapatite crystals (13). In fact, heritable extracellular PP i deficiencies are models of ectopic calcification such as ankylosing spinal hyperostosis and pathologic soft-tissue ossification (14-16). PP i is produced by the nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity of a family of isozymes that include PC-1, B10͞PDNP3, and autotaxin (17-19). However, PC-1 seems to be the only NTPPPH present in MVs (20). TNAP knockout (KO) mice (21-23) recapitulate the heritable metabolic disease hypophosphatasia (5), whereas PC-1-null mice display hypermineralization abnormalities similar to cartilage calcification in osteoarthritis (14) and ossification of the posterior longitudinal ligament of the spine (15).We previously identified PC-1 as the likely NTPPPH isozyme to act on the same pathway with TNAP as antagonistic regulators of extracellular PP i concentrations (20). In this paper, we have tested the hypothesis that bone abnormalities caused by the lack of TNAP could be counterbalanced by the removal of PC-1 and vice versa. We show that bone mineralization in double-KO mice lacking both TNAP and PC-1 is essentially normal, providing evidence that TNAP and PC-1 are key regulators of bone mineralization by determining the normal steady-state levels of PP i . Our work suggests that TNAP and PC-1 may be useful therapeutic targets for the treatment of bone mineralization abnormalities. Materials and MethodsAkp2 and Enpp1 KO Mice. The generation and characterization of the Akp2 KO mice has been reported (22,23). These Akp2 KO mice were hybrids of C57BL͞6 ϫ 129͞J mouse strains. The generation of the Enpp1 KO mice has been reported briefly (24). These Enpp1 KO mice were hybrids of C57BL͞6 ϫ 129͞SvTerJ mouse strains. Akp2͞Enpp1 double-heterozy...

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“…25 The entire coding region cDNA sequence of B10/PDNP3, and partial cDNA sequence of autotaxin (limited to domains encompassing the catalytic site and EF hand domain) also were determined using primers that spanned the cDNA regions, generating amplicons of 200 to 350 bp. All polymerase chain reaction products were electrophoretically separated, extracted, and then purified using Qiagen (Valencia, CA) gel extraction columns.…”

Section: Sequencing Of Pc-1 B10/pdnp3 and Autotaxinmentioning

confidence: 99%

PC-1 Nucleoside Triphosphate Pyrophosphohydrolase Deficiency in Idiopathic Infantile Arterial Calcification

Rutsch

Vaingankar²,

Johnson³

et al. 2001

The American Journal of Pathology

282

216

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Inogranic pyrophosphate (PPi) inhibits hydroxyapatite deposition, and mice deficient in the PPi-generating nucleoside triphosphate pyrophosphohydrolase (NTPPPH) Plasma cell membrane glycoprotein-1 (PC-1) develop peri-articular and arterial calcification in early life. In idiopathic infantile arterial calcification (IIAC), hydroxyapatite deposition and smooth muscle cell (SMC) proliferation occur, sometimes associated with peri-articular calcification. Thus, we assessed PC-1 expression and PPi metabolism in a 25-month-old boy with IIAC and peri-articular calcifications. Plasma PC-1 was <1 ng/ml by enzyme-linked immunosorbent assay in the proband, but 10 to 30 ng/ml in unaffected family members and controls. PC-1 functioned to raise extracellular PPi in cultured aortic SMCs. However, PC-1 was sparse in temporal artery lesion SMCs in the proband, unlike the case for SMCs in atherosclerotic carotid artery lesions of unrelated adults. Proband plasma and explant-cultured dermal fibroblast NTPPPH and PPi were markedly decreased. The proband was heterozygous at the PC-1 locus, and sizes of PC-1 mRNA and polypeptide, and the PC-1 mRNA-coding region sequence were normal in proband fibroblasts. However, immunoreactive PC-1 protein was relatively sparse in proband fibroblasts. Physiological extracellular matrix (ECM) calcification is limited to bones, teeth, and nonarticular (growth) cartilages.1,2 Moreover, ECM calcification must be tightly controlled, because normal calcium and phosphate concentrations in extracellular fluids are near the saturation point for the deposition of basic calcium phosphate crystals in the form of hydroxyapatite, and pathological calcification of the ECM can be observed in any tissue of the body.

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Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL)

Cited by 167 publications

References 19 publications

Increased trabecular bone formation in mice lacking the growth factor midkine

Increased trabecular bone formation in mice lacking the growth factor midkine

Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization

PC-1 Nucleoside Triphosphate Pyrophosphohydrolase Deficiency in Idiopathic Infantile Arterial Calcification

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