Mechanism of basic calcium phosphate crystal-stimulated matrix metalloproteinase-13 expression by osteoarthritic synovial fibroblasts: inhibition by prostaglandin E2

  title={Mechanism of basic calcium phosphate crystal-stimulated matrix metalloproteinase-13 expression by osteoarthritic synovial fibroblasts: inhibition by prostaglandin E2},
  author={Eamonn S. Molloy and Maria P. Morgan and George A. Doherty and Barry J. McDonnell and John M. O'Byrne and Desmond J. Fitzgerald and Geraldine Mccarthy},
  journal={Annals of the Rheumatic Diseases},
  pages={1773 - 1779}
Objective: To determine the mechanism of matrix metalloproteinase (MMP)-13 upregulation in osteoarthritic synovial fibroblasts (OASF) in response to stimulation with basic calcium phosphate (BCP) crystals and to investigate the effect of prostaglandin (PG)E2 on BCP crystal-stimulated MMP expression. Methods: Primary OASF were stimulated with BCP crystals; mRNA expression was measured by real-time reverse transcription–polymerase chain reaction and protein levels were assessed by Western… 

Mitogen-activated protein kinases as therapeutic targets in osteoarthritis

Understanding of the function of specific isoforms of the MAP kinases as well as upstream and downstream effectors may lead to the development of more specific inhibitors with less toxicity that could eventually be used as structure-modifying drugs for osteoarthritis.

Advances in understanding calcium-containing crystal disease

Animal models of osteoarthritis and in-vitro studies using calcium pyrophosphate dihydrate and basic calcium phosphate crystals will improve knowledge of these common crystals and could suggest new targets for drugs, as these common diseases are ‘orphan’ with respect to therapy.

Calcium-Containing Crystals and Osteoarthritis: an Unhealthy Alliance

Calcium-containing crystals induce key inflammatory pathways and may represent an attractive novel target in OA, a condition devoid of effective treatments.

Counterpoint: Hydroxyapatite crystal deposition is not intimately involved in the pathogenesis and progression of human osteoarthritis

This review critically examines the evidence from osteoarthritic synovial fluids, imaging, and histopathology to determine whether the well-characterized in vitro cellular reactions to hydroxyapatite apply to the pathogenesis of human osteo arthritis.

Point: Hydroxyapatite crystal deposition is intimately involved in the pathogenesis and progression of human osteoarthritis

Enhanced effort is needed to establish calcium-containing crystals as a therapeutic target in OA, as current data suggest an intimate association in its pathogenesis and progression.

Stimulation of Suicidal Erythrocyte Death by Increased Extracellular Phosphate Concentrations

It is hypothesized that suicidal erythrocyte death is triggered by complexed CaHPO4, an effect depending on extracellular but not intracellular Ca2+ concentration.

Pathological calcification in osteoarthritis: an outcome or a disease initiator?

Observations suggest that pathological calcification is most likely to be a disease initiator instead of an outcome of osteoarthritis progression, andhibiting pathological crystallite deposition within joint tissues therefore represents a potential therapeutic target in the management of osteOarthritis.



Molecular Mechanism of the Induction of Metalloproteinases 1 and 3 in Human Fibroblasts by Basic Calcium Phosphate Crystals

It is shown here that BCP crystal stimulation of M MP-1 and MMP-3 mRNA and protein expressions in human fibroblasts is dependent upon the calcium-dependent PKC signal transduction pathway and that the PKCα isozyme is specifically involved in the pathway.

Basic calcium phosphate crystals activate human osteoarthritic synovial fibroblasts and induce matrix metalloproteinase-13 (collagenase-3) in adult porcine articular chondrocytes

These data confirm the ability of BCP crystals to activate HOAS, leading to the induction of mitogenesis and MMP-1 production and suggest that B CP crystals act synergistically with IL1α and TNFα to promote MMP production and subsequent joint degeneration.

Induction of Matrix Metalloproteinase-8 in Human Fibroblasts by Basic Calcium Phosphate and Calcium Pyrophosphate Dihydrate Crystals: Effect of Phosphocitrate

The expression of MMP-8 in HF and its dose-dependent upregulation by basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPPD) crystals which arc markers of severe joint degeneration in ostcoarthritis are shown.

Basic calcium phosphate crystals induce synthesis and secretion of 92 kDa gelatinase (gelatinase B/matrix metalloprotease 9) in human fibroblasts

Fibroblast MMP-9 may be an important mediator of the joint destruction associated with synovial fluid BCP crystals as well as a concentration dependent induction of M MP-9 mRNA accumulation and protein secretion in human fibroblasts.

Basic calcium phosphate crystal-induced prostaglandin E2 production in human fibroblasts: role of cyclooxygenase 1, cyclooxygenase 2, and interleukin-1beta.

Findings indicate that BCP crystals may be an important amplifier of PGE(2) production through induction of the COX enzymes and the proinflammatory cytokine IL-1beta.

Prostaglandins E2 and E1 inhibit cytokine-induced metalloprotease expression in human synovial fibroblasts. Mediation by cyclic-AMP signalling pathway.

It is concluded that IL-1 beta stimulates MMP synthesis by activating PKC but not PKA, and that the synthesis of collagenase and stromelysin is discoordinate on a temporal and quantitative basis.

Octacalcium phosphate crystals directly stimulate expression of inducible nitric oxide synthase through p38 and JNK mitogen-activated protein kinases in articular chondrocytes

Direct activation of articular chondrocytes by OCP crystals is identified, which are the BCP crystals with the greatest potential for inducing inflammation and may be important in the pathogenesis of destructive arthropathies triggered by microcrystals.

Basic calcium phosphate crystals up-regulate metalloproteinases but down-regulate tissue inhibitor of metalloproteinase-1 and -2 in human fibroblasts.

The ability of BCP to induce the synthesis of degradative MMPs while down-regulating the synthesisof the naturally occurring counterpart TIMPs may explain the changes consistent with a role of B CP crystal in the pathogenesis of degenerative changes in osteoarthritis.