Pyrophosphate In Bone Research Articles

Augmented Fibroblast Growth Factor-23 Secretion in Bone Locally Contributes to Impaired Bone Mineralization in Chronic Kidney Disease in Mice.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism caused by CKD. Impaired bone mineralization together with increased bony secretion of fibroblast growth factor-23 (FGF23) are hallmarks of CKD-MBD. We recently showed that FGF23 suppresses the expression of tissue nonspecific alkaline phosphatase (TNAP) in bone cells by a Klotho-independent, FGF receptor-3-mediated signaling axis, leading to the accumulation of the mineralization inhibitor pyrophosphate. Therefore, we hypothesized that excessive FGF23 secretion may locally impair bone mineralization in CKD-MBD. To test this hypothesis, we induced CKD by 5/6 nephrectomy in 3-month-old wild-type (WT) mice and Fgf23−/−/VDRΔ/Δ (Fgf23/VDR) compound mutant mice maintained on a diet enriched with calcium, phosphate, and lactose. Eight weeks postsurgery, WT CKD mice were characterized by reduced bone mineral density at the axial and appendicular skeleton, hyperphosphatemia, secondary hyperparathyroidism, increased serum intact Fgf23, and impaired bone mineralization as evidenced by bone histomorphometry. Laser capture microdissection in bone cryosections showed that both osteoblasts and osteocytes contributed to the CKD-induced increase in Fgf23 mRNA abundance. In line with our hypothesis, osteoblastic and osteocytic activity of alkaline phosphatase was reduced, and bone pyrophosphate concentration was ~2.5-fold higher in CKD mice, relative to Sham controls. In Fgf23/VDR compound mice lacking Fgf23, 5/6-Nx induced secondary hyperparathyroidism and bone loss. However, 5/6-Nx failed to suppress TNAP activity, and bone pyrophosphate concentrations remained unchanged in Fgf23/VDR CKD mice. Collectively, our data suggest that elevated Fgf23 production in bone contributes to the mineralization defect in CKD-MBD by auto-/paracrine suppression of TNAP and subsequent accumulation of pyrophosphate in bone. Hence, our study has identified a novel mechanism involved in the pathogenesis of CKD-MBD.

FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner.

Fibroblast growth factor-23 (Fgf23) is a bone-derived hormone, suppressing phosphate reabsorption and vitamin D hormone (1,25(OH)2 D3 ) production in the kidney. It has long been an enigma why lack of Fgf23 or of Klotho, the coreceptor for Fgf23, leads to severe impairment in bone mineralization despite the presence of hypercalcemia and hyperphosphatemia. Using Fgf23(-/-) or Klotho(-/-) mice together with compound mutant mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor, we show that in Klotho(-/-) mice the mineralization defect is solely driven by 1,25(OH)2 D3 -induced upregulation of the mineralization-inhibiting molecules osteopontin and pyrophosphate in bone. In Fgf23(-/-) mice, the mineralization defect has two components, a 1,25(OH)2 D3 -driven component similar to Klotho(-/-) mice and a component driven by lack of Fgf23, causing additional accumulation of osteopontin. We found that FGF23 regulates osteopontin secretion indirectly by suppressing alkaline phosphatase transcription and phosphate production in osteoblastic cells, acting through FGF receptor-3 in a Klotho-independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization.

Klotho deficiency impairs mineralization by vitamin D hormone-driven upregulation of osteopontin and pyrophosphate in bone

Klotho deficiency impairs mineralization by vitamin D hormone-driven upregulation of osteopontin and pyrophosphate in bone

FGF-23 and secondary hyperparathyroidism in chronic kidney disease

The metabolic changes that occur in patients with chronic kidney disease (CKD) have a profound influence on mineral and bone metabolism. CKD results in altered levels of serum phosphate, vitamin D, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23); the increased levels of serum phosphate, PTH and FGF-23 contribute to the increased cardiovascular mortality in affected patients. FGF-23 is produced by osteocytes and osteoblasts and acts physiologically in the kidney to induce phosphaturia and inhibit the synthesis of 1,25-dihydroxyvitamin D3. PTH acts directly on osteocytes to increase FGF-23 expression. In addition, the high levels of PTH associated with CKD contribute to changes in bone remodelling that result in decreased levels of dentin matrix protein 1 and the release of low-molecular-weight fibroblast growth factors from the bone matrix, which stimulate FGF-23 transcription. A prolonged oral phosphorus load increases FGF-23 expression by a mechanism that includes local changes in the ratio of inorganic phosphate to pyrophosphate in bone. Other factors such as dietary vitamin D compounds, calcium, and metabolic acidosis all increase FGF-23 levels. This Review discusses the mechanisms by which secondary hyperparathyroidism associated with CKD stimulates bone cells to overexpress FGF-23 levels.

From polyphosphates to bisphosphonates and their role in bone and calcium metabolism.

This review will first describe the results obtained for the most part about 30-40 years ago on the effects and the possible role of pyrophosphate in bone and calcium metabolism. In a second part we shall describe how these results led to the development of a new class of compounds which are analogues of pyrophosphate, the bisphosphonates. The latter are today the main therapeutic drugs in the treatment of bone diseases characterized by increased osteolysis, such as Paget’s disease, tumor bone disease, and osteoporosis. Lastly, the possibility of using and extrapolating the intracellular effects of these compounds on the possible action of pyrophosphate and polyphosphates in the cell will be discussed.

The role of nucleoside triphosphate pyrophosphatase in the generation of inorganic pyrophosphate in bone and mineralizing cartilage

The role of nucleoside triphosphate pyrophosphatase in the generation of inorganic pyrophosphate in bone and mineralizing cartilage

Bone pyrophosphate in uremia and its association with extraosseous calcification.

The mean bone pyrophosphate was 0.360 +/- 0.15 mg/g in 8 controls and 1.22 +/- 1.39 mg/g bone in 27 uremic patients (P less than 0.0025). 13 of the 27 uremic patients had bone pyrophosphate levels greater than 2 SD above control values. The ash content of uremic bones with increased pyrophosphate levels (group II) was 56 +/- 9% as compared to 64 +/- 2% in control bones (P less than 0.01) and 60 +/- 7% in uremic bones having normal pyrophosphate levels (P less than 0.1) (group I). The magnesium content of bones in group II was 338 +/- 47 as compared to 211 +/- 13 (P less than 0.0005) in the controls and 294 +/- 73 mmol/kg ash (P less than 0.05) in group I. In group II, but not group I, there was a significant inverse correlation between duration of dialysis and percent bone ash (r = -0.59) (P less than 0.05). A definite relationship existed between elevated bone pyrophosphate levels and soft tissue calcification. In group II the mean pulmonary calcium content was 530 +/- 459 as compared to 32 +/- 26 mmol/kg/ash in group I (P less than 0.0025). All patients with a bone pyrophosphate level greater than 1.4 mg/g bone had extensive pulmonary calcification. It is concluded that the excess bone pyrophosphate present in some uremic patients is either deposited in the apatite crystal in the transphosphorylated form or else as the magnesium salt since the pyrophosphate is resistant to pyrophosphatase and surface adsorption of pyrophosphate is not altered by the increased bone pyrophosphate levels. The excess bone pyrophosphate could disturb bone calcification mechanisms in uremic patients. The association between increased bone pyrophosphate and soft tissue calcification suggests that the disordered pyrophosphate metabolism may be important in the pathogenesis of extraosseous calcification.

Effect of pyrophosphate on the exchangeable calcium pool of hydroxyapatite crystals

Pyrophosphate added to an equilibrated suspension of hydroxyapatite crystals caused a loss of calcium from the bulk solution without a loss of exchangeable calcium from the system. The evidence suggests that this loss was due to an entry of calcium into the hydration layer around the crystals. This redistribution of calcium was probably the result of the binding of pyrophosphate to the crystal surface. The changes showed that the binding of 2 μmoles of pyrophosphate was associated with the uptake of 1 μmole of calcium into the hydration layer from the bulk solution and a loss of 1 μmole of phosphate from the hydration layer into the bulk solution. The change in the distribution of exchangeable calcium after the addition of pyrophosphate was largely reversed by inorganic pyrophosphatase. These findings suggest that changes in the amount of pyrophosphate in bone in vivo might lead to changes in the distribution of the exchangeable calcium and thus might form a basis for a simple system for the minimization of fluctuations in the plasma calcium.