Protein geranylgeranylation controls collagenase expression in osteoarthritic cartilage

Sverdrup, Francis M.; Yates, Matthew; Vickery, Lillian; Klover, Jon A.; Song, Lily R.-H.; Anglin, C. P.; Misko, Thomas P.

doi:10.1016/j.joca.2010.03.015

Cited by 22 publications

(19 citation statements)

References 58 publications

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“…These observations suggest that some of the already existing small molecules that have demonstrated chondroprotective effects in vitro , in animal models and in humans with rheumatoid arthritis may constitute new treatment strategies to prevent the irreversible cartilage damage in the form of collagen loss after acute injury and thereby offer the hope of preventing future onset of injury related OA. These include: the biologic anti-cytokine therapies directed towards IL-1α, TNFα or IL-6 that are successful rheumatoid arthritis therapies [30]; p38 mitogen activated protein kinases (MAPK) pathway inhibitors, protective in a rat model of OA [31,32] and in explant culture [33]; statins that inhibit cartilage breakdown by reducing protein prenylation [34,35]; and sulfazalazine that can inhibit collagenase production by inhibiting the NFkB pathway in cartilage explant models [36]. Direct inhibition of catabolic enzymes may also be a viable short term target for cartilage and joint protection after acute injury.…”

Section: Discussionmentioning

confidence: 99%

Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254)

et al. 2010

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IntroductionAcute trauma involving the anterior cruciate ligament is believed to be a major risk factor for the development of post-traumatic osteoarthritis 10 to 20 years post-injury. In this study, to better understand the early biological changes which occur after acute injury, we investigated synovial fluid and serum biomarkers.MethodsWe collected serum from 11 patients without pre-existing osteoarthritis from a pilot intervention trial (5 placebo and 6 drug treated) using an intra-articular interleukin-1 receptor antagonist (IL-1Ra) therapy, 9 of which also supplied matched synovial fluid samples at presentation to the clinic after acute knee injury (mean 15.2 ± 7.2 days) and at the follow-up visit for reconstructive surgery (mean 47.6 ± 12.4 days). To exclude patients with pre-existing osteoarthritis (OA), the study was limited to individuals younger than 40 years of age (mean 23 ± 3.5) with no prior history of joint symptoms or trauma. We profiled a total of 21 biomarkers; 20 biomarkers in synovial fluid and 13 in serum with 12 biomarkers measured in both fluids. Biomarkers analyzed in this study were found to be independent of treatment (P > 0.05) as measured by Mann-Whitney and two-way ANOVA.ResultsWe observed significant decreases in synovial fluid (sf) biomarker concentrations from baseline to follow-up for sfC-Reactive protein (CRP) (P = 0.039), sflubricin (P = 0.008) and the proteoglycan biomarkers: sfGlycosaminoglycan (GAG) (P = 0.019), and sfAlanine-Arginine-Glycine-Serine (ARGS) aggrecan (P = 0.004). In contrast, we observed significant increases in the collagen biomarkers: sfC-terminal crosslinked telopeptide type II collagen (CTxII) (P = 0.012), sfC1,2C (P = 0.039), sfC-terminal crosslinked telopeptide type I collagen (CTxI) (P = 0.004), and sfN-terminal telopeptides of type I collagen (NTx) (P = 0.008). The concentrations of seven biomarkers were significantly higher in synovial fluid than serum suggesting release from the signal knee: IL-1β (P < 0.0001), fetal aggrecan FA846 (P = 0.0001), CTxI (P = 0.0002), NTx (P = 0.012), osteocalcin (P = 0.012), Cartilage oligomeric matrix protein (COMP) (P = 0.0001) and matrix metalloproteinase (MMP)-3 (P = 0.0001). For these seven biomarkers we found significant correlations between the serum and synovial fluid concentrations for only CTxI (P = 0.0002), NTx (P < 0.0001), osteocalcin (P = 0.0002) and MMP-3 (P = 0.038).ConclusionsThese data strongly suggest that the biology after acute injury reflects that seen in cartilage explant models stimulated with pro-inflammatory cytokines, which are characterized by an initial wave of proteoglycan loss followed by subsequent collagen loss. As the rise of collagen biomarkers in synovial fluid occurs within the first month after injury, and as collagen loss is thought to be irreversible, very early treatment with agents to either reduce inflammation and/or reduce collagen loss may have the potential to reduce the onset of future post-traumatic osteoarthritis.Trial registrationThe samples used in this study were deriv...

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Section: Discussionmentioning

confidence: 99%

Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254)

et al. 2010

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“…Some studies suggest that statins modulate chondrocyte metabolism by reducing prenylation of key signaling molecules that control expression of collagen-degrading enzymes [25]. Among statin derivates, simvastatin had the advantage of lipophilic properties and the ability to passively diffuse into cells at a dose-dependent rate.…”

Section: Discussionmentioning

confidence: 99%

Mechanically induced experimental knee osteoarthritis benefits from anti-inflammatory and immunomodulatory properties of simvastatin via inhibition of matrix metalloproteinase-3

Aktaş

Şener

Göçün

2011

J Orthopaed Traumatol

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BackgroundWe investigated the anti-inflammatory and immunomodulatory effect of simvastatin on articular cartilage via the inhibition of matrix metalloproteinase-3 (MMP-3), a matrix-degrading enzyme, in a mechanically induced experimental osteoarthritis (OA) animal model.Materials and methodsTwenty-seven albino Wistar rats were divided in three groups of equal number. Unphysiologic loading of articular cartilage was simulated by transecting anterior cruciate ligaments of the right knees of 18 rats consisting of groups 1 and 2. Nine animals in group 2 received orally administered simvastatin 20 mg/kg per day by gavage for 8 weeks. Animals in group 3 were sham operated. All animals were sacrificed at postoperative 8 weeks. Effects of simvastatin on disease progression was evaluated by documenting OA changes in cartilage specimens using Osteoarthritis Research Society International (OARSI) OA cartilage histopathology assessment system scores combined with the percentage of MMP-3 expression in chondrocytes.ResultsSimvastatin treatment significantly down-regulated the percentage of MMP-3 expression in chondrocytes as assessed by immunohistochemistry methods. Suppression of this matrix-degrading enzyme by simvastatin also reduced OARSI scores, suggesting the potential for statins against OA progression.ConclusionsFollowing knee trauma, OA initiates at the molecular level in a short period of time. Irreversible structural changes in cartilage that require demanding treatment strategies led us to focus on effective measures to prevent OA. Statins have immunomodulatory and anti-inflammatory properties independent from their serum-cholesterol-lowering effects. One of these widely used drugs, simvastatin, showed beneficial effects on OA progression and extent by reducing cartilage degradation in our experimental setting. If these results are confirmed by human trials, simvastatin might be considered by orthopedic surgeons as a disease-modifying drug during the early inflammatory phase of posttraumatic OA.

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“…However, cholesterol biosynthesis plays an important role in chondrogenesis [28,29]. Accordingly, these beneficial effects of statins have been related to reduced protein geranylgeranylation rather than inhibition of cholesterol synthesis itself [60,62]. …”

Section: Lipids In Osteoathritic Cartilagementioning

confidence: 99%

Lipid Transport and Metabolism in Healthy and Osteoarthritic Cartilage

Villalvilla

Gómez

Largo

et al. 2013

IJMS

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Cartilage is an avascular tissue and cartilage metabolism depends on molecule diffusion from synovial fluid and subchondral bone. Thus, nutrient availability is limited by matrix permeability according to the size and charge of the molecules. Matrix composition limits the access of molecules to chondrocytes, determining cell metabolism and cartilage maintenance. Lipids are important nutrients in chondrocyte metabolism and are available for these cells through de novo synthesis but also through diffusion from surrounding tissues. Cartilage status and osteoarthritis development depend on lipid availability. This paper reviews lipid transport and metabolism in cartilage. We also analyze signalling pathways directly mediated by lipids and those that involve mTOR pathways, both in normal and osteoarthritic cartilage.

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Protein geranylgeranylation controls collagenase expression in osteoarthritic cartilage

Cited by 22 publications

References 58 publications

Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254)

Changes in serum and synovial fluid biomarkers after acute injury (NCT00332254)

Mechanically induced experimental knee osteoarthritis benefits from anti-inflammatory and immunomodulatory properties of simvastatin via inhibition of matrix metalloproteinase-3

Lipid Transport and Metabolism in Healthy and Osteoarthritic Cartilage

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