Mechanism of Calcification: Inhibitory Role of Pyrophosphate

Fleisch, H.; Bisaz, S.

doi:10.1038/195911a0

Cited by 243 publications

(128 citation statements)

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“…(48,49) In addition to their functions outside the skeleton, however, both Ank and Enpp1 appear to be directly involved in the promotion of bone mineralization, which is best underscored by the finding that either Ank or Enpp1 deficiency partially rescues the skeletal mineralization defects of mice lacking tissue-nonspecific alkaline phosphatase. (50,51) Moreover, inactivating mutations of both genes have been reported to result in skeletal phenotypes that share at least some similarities to Mdk-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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show abstract

“…Pyrophosphate and related polyphosphates, such as hexametaphosphate, have also been extensively used as toothpaste additives to prevent dental calculus formation and as food additives. However, it was the pioneering work of Fleisch and colleagues in the 1960s that identified the ability of pyrophosphate to inhibit biomineralisation [4][5][6][7].…”

Section: Extracellular Pyrophosphate: the "Early Years"mentioning

confidence: 99%

“…They discovered that pyrophosphate potently antagonises the ability of calcium to crystallise with phosphate to form hydroxyapatite (Ca10(PO4)(OH2)) [5,7]. Pyrophosphate also binds stongly to the surface of hydroxyapatite crystals and blocks their ability to act as a nucleator for mineralisation therefore preventing further crystal growth [8].…”

Section: Extracellular Pyrophosphate: the "Early Years"mentioning

confidence: 99%

“…As originally highlighted by Fleisch and Neuman [4][5][6][7], body fluids are supersaturated with respect to calcium and phosphate, and mineralisation is facilitated by the presence of nucleating agents. Their pioneering studies identified collagen as an important nucleator, and they showed that the maintenance of supersaturated levels of calcium and phosphate was achieved by the presence of inhibitors.…”

Section: Biological Mineralisation and The Role Of Pyrophosphate As Amentioning

confidence: 99%

“…Their pioneering studies identified collagen as an important nucleator, and they showed that the maintenance of supersaturated levels of calcium and phosphate was achieved by the presence of inhibitors. The key inhibitor was destroyed by alkaline phosphatase and proved to be pyrophosphate [4][5][6][7].…”

Section: Biological Mineralisation and The Role Of Pyrophosphate As Amentioning

confidence: 99%

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