Shock absorbers: Boning up on citrate

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  • Published: Apr 1, 2014
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Shock absorbers: Boning up on citrate

Citrate cycling

A combination of X-ray diffraction, NMR spectroscopy, imaging and high-level molecular modelling by a team at the University of Cambridge has demonstrated that citrate ions form a shock-absorbing gel between crystals within the structure of bone.

A combination of X-ray diffraction, NMR spectroscopy, imaging and high-level molecular modelling by a team at the University of Cambridge and University College London has demonstrated that citrate ions form a shock-absorbing gel between crystals within the structure of bone. This allows the crystals to slip across each other when the bone is under stress and so reduces the risk of the bone shattering.

Citrate, the ion of citric acid, is an intermediate in the tricarboxylic acid cycle (TCA cycle), the Kreb's cycle. However, the new work suggests that it is another role when it mixes with water it forms a viscous fluid that is intercalated between the nanoscale calcium phosphate crystals of bone. If citrate leaks out, the crystals can fuse into bigger and bigger aggregates that reduce the bone's flexibility making it increasingly brittle and more likely to shatter. Chemists at Cambridge suggest that this process may well be the underlying process giving rise to osteoporosis.

Melinda Duer and her colleagues suggest that their findings might require a paradigm shift in our perspective on bone pathology. The work may lead to revisions of our understanding of osteoporosis, brittle bone diseases and other bone problems. The team outlines details in the journal Proceedings of the National Academy of Sciences.

Flat-packed crystals

"Bone mineral was thought to be closely related to hydroxyapatite. But what we've shown is that a large part of bone mineral - possibly as much as half of it in fact - is made up of the citrate gel between mineral crystals," Duer explains. "This nanoscopic layering of citrate fluid and mineral crystals in bone means that the crystals stay in flat, plate-like shapes that have the facility to slide with respect to each other. Without citrate, all crystals in bone mineral would collapse together, become one big crystal and shatter. It's this layered structure that's been missing from our knowledge, and we can now see that without it you're stuffed."

Chemical control

Citrate is a chelating ion with four arms that can bond readily to the abundance of calcium found in bone. Its structure allows the citrate to hold bone's mineral crystals together without allowing them to fuse and simultaneously trapping water between the plates to allow slippage. Calcium is actually delivered to living bone pre-wrapped within citrate to preclude direct formation of phosphate bonds in the wrong locations. Bone contains a porous, protein mesh within which calcium is deposited. In healthy bone, the holes are very small and deposition of citrate with calcium occurs normally. As people age or suffer repeated bone trauma, the protein mesh is compromised and repair processes lead to widening of the pores in the bone, which allows the citrate fluid to escape and crystals to fuse inappropriately as biological control is lost and simple chemistry takes over.

"Pretty much the moment calcium and phosphate touch, they form a solid," Duer explains. "You end up with these expanding clumps of brittle crystal, with water and citrate relegated to the outside of them." She adds that, "In terms of chemistry, that solid clump of mineral is the most stable structure. Biomechanically, however, it's hopeless - as soon as you stand on it, it shatters. If we want to cure osteoporosis, we need to figure out how to stop the bigger holes forming in the protein matrix." The team has follow-up studies in place and hope to publish subsequent findings in rapid succession over the course of the coming year.

"We have two things we're doing now," Duar told SpectroscopyNOW. "One is to find out what causes larger spaces to occur in collagen matrices (we are working on the hypothesis that advanced glycation end-products (AGEs) may well have something to do with it) and the other is to detail the structure of the mineral that forms in different-sized holes, so that we can work out at what point deficiencies in the collagen matrix are likely to become a problem. We're hoping that the eventual outcome will be that we can clearly define some druggable targets that would slow or even halt the progression of diseases like osteoporosis."

Related Links

Proc Natl Acad Sci, 2014, online: "Citrate bridges between mineral platelets in bone"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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