PPi Ions Research Articles

Synthesis and squalene synthetase inhibitory activity of tripotassium 1-methyl-1-[( N-benzyl- N-farnesyl)aminoethylphosphinato]ethylphosphonate as a tethered analog of N-benzyl- N-farnesylamine-inorganic pyrophosphate ion pair

Synthesis and squalene synthetase inhibitory activity of tripotassium 1-methyl-1-[ N-benzyl- N-farnesyl)aminoethylphosphinato]ethylphosphonate ( 2) as a tethered analog of N-benzyl- N-farnesylamine( 1)-PPi ion pair, using phosphinato(dimethylmethyl)phosphonate as a PPi mimic, is described.

Calcium Pyrophosphate Crystal Deposition in Model Systems

The chemistry and molecular bonding characteristics of the CaPPi family of compounds are very complex. The unique molecular flexibility of the PPi anion and the potential variability of Ca coordination geometries have allowed for a broad spectrum of CaPPi type structures. The structure of t-CPPD has the smallest P-OB-P angle of the known CaPPi structures, both Ca atoms are 7 coordinate which is the maximum allowable contacts for Ca atoms, and the two water molecules of crystallization not only serve to fill molecular space, but they are also involved in direct contact to the PPi anions and the Ca atoms. The structure of t-CPPD appears to be very stable and the structural characteristics support the observation that the crystals are sparingly soluble in an aqueous environment. Unfortunately, the structure of m-CPPD is not known and comparisons cannot be made. The solution model studies have resulted in the observation that t-CPPD and m-CPPD crystals can be grown in an aqueous environment at conditions far less harsh than those required for the standard synthetic procedure. However, the synthetic procedure, in contrast to the solution models, yields the prismatic crystal growth morphology of t-CPPD and the rod morphology of m-CPPD observed in vivo. The solution models showed that increasing Mg or Pi retarded crystal formation. At physiologic levels of Mg and Pi, a-CaPPi formed, but neither t-CPPD nor m-CPPD would form. In all solution studies, the final Ca and PPi were not determined and therefore a correlation could not be made between the ionic concentrations and crystal type formed. The gel models using silica, polyacrylamide, and biologic grade gelatin all highlighted that the time of incubation of Ca and PPi ions was a critical parameter in determining the type of crystal formed. The biologic grade gelatin model studies that we conducted indicated that the formation of the two in vivo crystals was mediated by the formation of intermediate crystalline materials and the subsequent dissolution of those species. This formation/dissolution/reformation mechanism allows for a very localized ionic concentrating process to occur. In our model system, we measured the final Ca and PPi levels at all points of crystallization and could map the ionic concentration gradients and compare them to the crystal type formed with respect to the time of incubation. However, the crystal growth morphologies for t-CPPD and m-CPPD still did not match the morphologies observed in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Extrusion of pyrophosphate into extracellular media by osteoarthritic cartilage incubates.

The distribution of calcium pyrophosphate mineral phase, almost exclusively confined to articular cartilage in chondrocalcinosis, and the high level of pyrophosphate (PPi) ion relative to serum in synovial fluid in patients with either chondrocalcinosis or advanced osteoarthritis led to an investigation of whether cartilage cells elaborate PPi ions. Incubates of articular cartilage from young rabbits but not from mature rabbits, as well as growth plates cartilage, released PPi into incubation media during a 4h period. Control rabbit ear cartilage and synovial membrane elaborated negligible amounts of PPi. The PPi was shown to be undialyzable but could be dissociated from the alkaline phosphatase by ultracentrifugation. In 16 patients with osteoarthritis, a substantial output of PPi by samples of articular cartilage from the knee was demonstrated. It is postulated that either rapid cell division and matrix synthesis found in the base of ulcerating osteoarthritic cartilage or remodeling calcified sites are the source of the PPi in such osteoarthritic cartilage. It is further hypothesized that this PPi output accounts at least in part for the elevated PPi levels found in synovial fluid of patients with osteoarthritis.