Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.4.1 (
phosphodiesterase
)
18,767
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities and functions remain unclear. Alkaline phosphatase (TNAP) plays a crucial role promoting mineralization of the extracellular matrix by restricting the concentration of the calcification inhibitor inorganic pyrophosphate (PP(i)). Mutations in the TNAP gene cause hypophosphatasia, a heritable form of rickets and osteomalacia. Here we show that
PHOSPHO1
, a phosphatase with specificity for phosphoethanolamine and phosphocholine, plays a functional role in the initiation of calcification and that ablation of
PHOSPHO1
and TNAP function prevents skeletal mineralization. Phospho1(-/-) mice display growth plate abnormalities, spontaneous fractures, bowed long bones, osteomalacia, and scoliosis in early life. Primary cultures of Phospho1(-/-) tibial growth plate chondrocytes and chondrocyte-derived matrix vesicles (MVs) show reduced mineralizing ability, and plasma samples from Phospho1(-/-) mice show reduced levels of TNAP and elevated plasma PP(i) concentrations. However, transgenic overexpression of TNAP does not correct the bone phenotype in Phospho1(-/-) mice despite normalization of their plasma PP(i) levels. In contrast, double ablation of
PHOSPHO1
and TNAP function leads to the complete absence of skeletal mineralization and perinatal lethality. We conclude that
PHOSPHO1
has a nonredundant functional role during endochondral ossification, and based on these data and a review of the current literature, we propose an inclusive model of skeletal calcification that involves intravesicular
PHOSPHO1
function and P(i) influx into MVs in the initiation of mineralization and the functions of TNAP, nucleotide pyrophosphatase
phosphodiesterase
-1, and collagen in the extravesicular progression of mineralization.
...
PMID:Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification. 2068 22
Mineralization is a key process in the formation of bone and cartilage in vertebrates, involving the deposition of calcium- and phosphate-containing hydroxyapatite (HA) mineral within a collagenous matrix. Inorganic phosphate (P
i
) accumulation within matrix vesicles (MVs) is a fundamental stage in the precipitation of HA, with
PHOSPHO1
being identified as the principal enzyme acting to produce P
i
PHOSPHO1
is a dual-specific phosphocholine/phosphoethanolamine phosphatase enriched in mineralizing cells and within MVs. However, the source and mechanism by which
PHOSPHO1
substrates are formed before mineralization have not been determined. Here, we propose that 2 enzymes-phospholipase A2 (PLA
2
) and ectonucleotide pyrophophatase/
phosphodiesterase
6 (ENPP6)-act in sequence upon phosphatidylcholine found in MV membranes to produce phosphocholine, which
PHOSPHO1
can hydrolyze to liberate P
i
This hypothesis is supported by evidence that both enzymes are expressed in mineralizing cells and data showing that phosphatidylcholine is broken down in MVs during mineralization. Therefore, PLA
2
and ENPP6 activities may represent a key step in the mineralization process. Further functional studies are urgently required to examine their specific roles in the initiation of skeletal mineralization.-Stewart, A. J., Leong, D. T. K., Farquharson, C. PLA
2
and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization.
...
PMID:PLA
2
and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization. 2886 58
Bone mineralization is initiated by matrix vesicles, small extracellular vesicles secreted by osteoblasts, inducing the nucleation and subsequent growth of calcium phosphate crystals inside. Although calcium ions (Ca
2+
) are abundant throughout the tissue fluid close to the matrix vesicles, the influx of phosphate ions (PO4
3-
) into matrix vesicles is a critical process mediated by several enzymes and transporters such as ecto-nucleotide pyrophosphatase/
phosphodiesterase
1 (ENPP1), ankylosis (ANK), and tissue nonspecific alkaline phosphatase (TNSALP). The catalytic activity of ENPP1 in osteoblasts generates inorganic pyrophosphate (PPi) intracellularly and extracellularly, and ANK may allow the intracellular PPi to pass through the plasma membrane to the outside of the osteoblasts. Although the extracellular PPi binds to growing hydroxyapatite crystals to prevent crystal overgrowth, TNSALP on the osteoblasts and matrix vesicles hydrolyzes PPi into PO4
3-
monomers: the prevention of crystal growth is blocked, and PO4
3-
monomers are supplied to matrix vesicles. In addition,
PHOSPHO1
is thought to function inside matrix vesicles to catalyze phosphocoline, a constituent of the plasma membrane, consequently increasing PO4
3-
in the vesicles. Accumulation of Ca
2+
and PO4
3-
inside the matrix vesicles then initiates crystalline nucleation associated with the inner leaflet of the matrix vesicles. Calcium phosphate crystals elongate radially, penetrate the matrix vesicle's membrane, and finally grow out of the vesicles to form calcifying nodules, globular assemblies of needle-shaped mineral crystals retaining some of those transporters and enzymes. The subsequent growth of calcifying nodules appears to be regulated by surrounding organic compounds, finally leading to collagen mineralization.
...
PMID:Ultrastructure and biological function of matrix vesicles in bone mineralization. 2941 Nov 3
