Contribution of calcium-containing crystals to cartilage degradation and synovial inflammation in osteoarthritis.
OBJECTIVE
The role of calcium phosphate and pyrophosphate crystals in osteoarthritis (OA) is unclear: are they a symptom of the damage that occurs to the joint or a key intermediate in the progression of inflammation and joint damage that occurs in OA? The proinflammatory and catabolic response of synthetic calcium phosphate and pyrophosphate crystals and crystals extracted from human osteoarthritic knee cartilage has been investigated. The crystal forms eliciting a response have been characterised allowing a comparison of the biological effects of synthetic and native calcium crystals on human osteoarthritic chondrocytes and synoviocytes to be carried out.


METHODS
Calcium phosphate and pyrophosphate crystals were synthesised in vitro and their crystal forms characterised by X-ray powder diffraction (XRPD). The inorganic crystalline material present in human osteoarthritic cartilage was extracted and its structural composition elucidated by XRPD. These crystals were applied to human primary osteoarthritic chondrocytes and synoviocytes and the production of proinflammatory and catabolic mediators measured.


RESULTS
The crystals extracted from human osteoarthritic knee cartilage were identified as consisting of a mixture of monoclinic and triclinic calcium pyrophosphate dihydrate (m-CPPD and t-CPPD). These crystals elicited an inflammatory and catabolic response in human primary osteoarthritic chondrocytes and synoviocytes as measured by an increase in nitric oxide (NO), matrix metalloproteinase 13 (MMP-13) and prostaglandin E2 (PGE(2)) production. NO, MMP-13 and PGE(2) production was also increased when the synthetic calcium hydrogen phosphate dihydrate (DCPD) and calcium pyrophosphate hydrates were applied to the cells.


CONCLUSIONS
Crystals extracted from human osteoarthritic knee cartilage induce the production of proinflammatory and catabolic mediators (NO, MMP-13 and PGE(2)) in human primary chondrocytes and synoviocytes. Synthetic calcium phosphate and pyrophosphate crystals elicit a similar response in those cells. Our findings suggest that these crystals could contribute to cartilage degradation and synovitis in OA.
Liu
Y Z
YZ
Department of Bioscience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, UK. yu-zhen.liu@astrazeneca.com
Jackson
A P
AP
Cosgrove
S D
SD
D015415:Biomarkers / Q000378:metabolism; D002130:Calcium Phosphates / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D002131:Calcium Pyrophosphate; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D002805:Chondrocalcinosis / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D003460:Crystallization; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism*; D014961:X-Ray Diffraction
D015415:Biomarkers; D002130:Calcium Phosphates; D009569:Nitric Oxide; D053509:Matrix Metalloproteinase 13; D015232:Dinoprostone; D002131:Calcium Pyrophosphate