The matrix metalloproteinases as pharmacological target in osteoarthritis: Statins may be of therapeutic benefit

doi:10.1016/j.mehy.2007.01.042

Medical Hypotheses

Volume 69, Issue 3, 2007, Pages 557-559

https://doi.org/10.1016/j.mehy.2007.01.042 Get rights and content

Summary

Osteoarthritis (OA) is a common joint disease; however, current pharmacologic agents for OA are only symptomatic and they can not prevent the disease progression. Matrix metalloproteinases (MMPs) produced by chondrocytes play an important role in the development of cartilage destruction in OA, and agents that can target against MMPs activity may be of therapeutical value. There were reports that statins can inhibit the secretion of MMPs in vitro and in vivo, which were believed to account for the plaque stabilizing effects of statins in the treatment of atherosclerosis. We based our hypothesis on that atherosclerosis possesses some aspects that are similar to that of osteoarthritis, such as inflammation and matrix degradation. Since statins have displayed great benefits in modifying the progression of atherosclerosis via anti-inflammatory and matrix-stabilizing mechanisms, it is conceivable that statins may also prevent the disease progression of osteoarthritis. Further work are needed to verify if statins can protect cartilage from destruction through inhibition of MMP secretion by chondrocytes, and their potential to be used as therapeutic agents in OA should be investigated.

Introduction

Osteoarthritis (OA) is the most common joint disease for middle aged and older people. It is characterized by joint pain and dysfunction; and, in its advanced stages, joint contractures, muscle atrophy and limb deformity. It occurs through several complex mechanisms such as progressive erosion of cartilage, remodeling and sclerosis of subchondral bone, and osteophyte formation, leading to a progressive destruction of joints and functional loss. The pathophysiology of the joint degeneration that leads to the clinical syndrome of OA remains poorly understood.

Current treatments are only symptomatic and do not prevent or cure OA. Once patients develop OA, they suffer from the disease for the rest of their lives. The high frequency and chronicity of OA and the lack of effective preventive measures or cures make this disease a substantial economic burden for patients and health care systems. Finding of agents that can inhibit or slow the degeneration of cartilage will improve the treatment of OA. But until now there were no such agents that have been proved effective clinically [1].

Section snippets

Cartilage degeneration in osteoarthritis

OA is characterized by progressive loss of articular cartilage, the main components of which is collagen and proteoglycan [2]. In the OA affected joint, there is an imbalance between the synthesis and degradation of articular cartilage matrix, which is believed to be a consequence of mechanical and biochemical events [3]. Chondrocytes regulate cartilage metabolism under both normal and pathological conditions. These cells initiate the rapid degradation of proteoglycan from cartilage in response

MMPs in osteoarthritis

In OA, the degradation of extracellular matrix is driven mainly by enzymes from the chondrocytes. The enzymatic activity have been studied in OA cartilage from multiple animal models of early and late OA, and in late stage OA cartilage obtained at joint replacement. Most evidence suggests that matrix degradation is achieved through the action of MMPs, a family of enzymes that contain zinc at the catalytic site and cleave components at physiological pH and temperature. In cartilage, the major

Statins inhibit MMPs secretion

Statins are inhibitor of the rate-determining enzyme in the biosynthesis of cholesterol and are initially used as anti-hyperlipidemic agents in human [7]. But now they are more widely used to prevent acute fatal events in cardiovascular patients, due to the fact that they can stabilize the atherosclerotic plaque and reduces mortality in cardiovascular diseases. The mechanism is that statins can increase collagen content in the fibrous cap of atherosclerotic plaques by inhibiting MMP secretion

Can statins be used to treat osteoarthritis?

Recent evidence has shown that statins possess a variety of biological properties, other than lipid lowering abilities, including immunomodulating and anti-inflammatory effects. In particular, these agents have been shown to inhibit the production of cytokines such as IL-6, IL-8 and MCP-1; a recent report showed that simvastatin markedly inhibited collagen induced arthritis in a murine model. Thus, statins may reasonably play a role in chronic inflammatory conditions, such as rheumatic

Conclusion

In summary, statins may have the ability to inhibit inflammation induced matrix catabolism, the mechanism of which may be related to inhibition of MMPs secretion. Therefore, statins might have potential to be used as therapeutic agents in OA.

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Cited by (25)

Vitamin D reduces pain and cartilage destruction in knee osteoarthritis animals through inhibiting the matrix metalloprotease (MMPs) expression
2023, Heliyon
In this study, we investigated the therapeutic potential of vitamin D (VITD) in OA Wistar rats induced by anterior cruciate ligament transection combined with medial meniscectomy (ACLT + MMx). In ACLT + MMx-induced OA rats, pain severity, cartilage destruction, inflammatory cytokines, and MMPs were all measured.
ACLT + MMx methods were used to induce OA, and pain behavioral studies such as the weight bearing test and paw withdrawal test were performed while the knee width and body weights were also measured. Furthermore, Hematoxylin and Eosin (H&E) staining was used to determine knee histopathological studies, as well as OARSI scoring, cartilage thickness, cartilage width, and cartilage degradation scores. The enzyme-linked immunosorbent assay (ELISA) studies were used to check the serum levels of VITD, C-telopeptide of Type II collagen (CTX-II), and pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and anti-inflammatory cytokines interleukin-10 (IL-10), and MMPs (MMP-3, MMP-9, and MMP-13). Finally, the reverse transcription polymerase chain reaction (RT-PCR) test was used to determine the levels of MMPs, nuclear factor-kappa B (NF-κB), TNF-α, IL-6, and IL-10 in IL-1β stimulated chondrocytes.
The oral VITD supplement significantly reduced OA pain, inflammation, cartilage destruction, and MMPs levels. Furthermore, serum VITD levels increased while CTX-II levels decreased, indicating that VITD reduced cartilage degradation effectively. Moreover, VITD supplementation reduced the expression of pro-inflammatory TNF-α, IL-1β, and IL-6 cytokines while increasing the expression of anti-inflammatory IL-10. The elevation of MMPs after ACLT + MMx surgery contributed to articular cartilage destruction, which was reduced by VITD supplementation. Finally, VITD supplementation significantly reduces serum levels of MMPs, IL-1β, TNF-α, and IL-6 while increasing IL-10 levels. Then, using the in-vitro cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) MTT assay, examine the cytotoxicity profile of VITD in rat chondrocytes after stimulated with IL-1β, which shows no toxicity in the dose range of VITD 0–500 IU. Finally, RT-PCR studies in IL-1β stimulated rat chondrocytes revealed that VITD (50, 100, and 500 IU) significantly reduced the mRNA levels of MMPs, NF-κB, TNF-α, and IL-6, while increasing IL-10 levels, indicating that VITD reduced chondrocyte destruction and overcame harsh conditions in a dose-dependent manner.
Overall, the in vivo and in vitro findings show that VITD effectively reduces OA pain, inflammation, and chondrocyte destruction by lowering MMPs levels specifically.
Diagnostic value of matrix metalloproteinases-1, −3 and −13 in patients with primary knee osteoarthritis: Relation to radiological severity
2023, Egyptian Rheumatologist
Citation Excerpt :
Matrix metalloproteinases (MMPs) are extracellular endopeptidases that cleave extracellular matrix (ECM) substrates such as collagen, fibronectin, proteoglycan and laminin [6]. MMPs synthesised by chondrocytes significantly contribute to cartilage destruction in OA; thus, substances that can inhibit MMP action may be therapeutically valuable [7]. MMP-1, also known as collagenase-1, is the main enzyme responsible for cleaving type II collagen, which is a major constituent of the ECM.
Knee osteoarthritis (KOA) is an important cause of disability in elderly. Aim of the work: to study the expression of matrix metalloproteinases (MMP-1, MMP-3 and MMP-13) in serum of patients with KOA and relation to radiological findings.
One hundred patients with KOA and 80 matching control were studied. The Kellegren Lawrence (KL) scale was assessed. The mRNA and protein expressions of MMP-1, MMP-3 and MMP-13 were assessed by “quantitative real-time polymerase chain reaction (qRT-PCR)” and western blotting, respectively.
There was a significant increase in the mRNA expression of MMP-1, MMP-3 and MMP-13 in patients (18.5 ± 3.4, 3 ± 0.5 and 2 ± 0.2, respectively) compared to controls (2.6 ± 0.4, 0.7 ± 0.3 and 0.3 ± 0.06, respectively)(all p < 0.001) and in the protein expression of MMP-1, MMP-3 and MMP-13 in patients (2.89 ± 0.01, 2.37 ± 0.07, 2.56 ± 0.02, respectively) relative to controls (1.15 ± 0.04, 0.79 ± 0.01, 1.02 ± 0.08 respectively (all p < 0.001). A significant correlation was found between the age of patients and mRNA expression of MMP-1 (r = 0.19, p = 0.01) and MMP-3 (r = 0.17, p = 0.019) and between the BMI and mRNA expression of MMP-1 (r = 0.16, p = 0.028). No significant correlation was found between mRNA expression of MMP-1, MMP-3 and MMP-13 and grade of KOA. At cut off values 5.5, 1.7 and 0.8, MMP-1, MMP-3 and MMP-13 could diagnose KOA at a sensitivity of 98 %, 100 % and 100 % respectively with 100 % specificity for all.
The expression of MMP-1, MMP-3 and MMP-13 could be a valuable non-invasive marker for early diagnosis of primary KOA with no relation to radiological finding.
Pravastatin ameliorated osteoarthritis susceptibility in male offspring rats induced by prenatal ethanol exposure
2021, Bone
Osteoarthritis (OA) is a disease associated with a disorder of cholesterol metabolism. Our previous studies showed that prenatal ethanol exposure (PEE) caused cholesterol accumulation in articular cartilage and increased the susceptibility to OA in offspring. However, we did not determine whether pravastatin, a cholesterol-lowering agent, could rescue PEE-induced susceptibility to OA. Here, fetal rats were divided into a PEE group and a control group during pregnancy. At postnatal week (PW) 8, sixteen male offspring rats from both groups were injected papain through the articular cavity. Eight of them from each group were treated with pravastatin (20 mg/kg·d) by gavage for four weeks simultaneously. We found that pravastatin ameliorated papain-induced high expression of inflammatory factors [interleukin (IL)-1, IL-6], matrix degradation enzymes [matrix metalloproteinase (MMP)-3, MMP-13], and apoptosis factors (caspase-3 and caspase-8) in the cartilage of the PEE group. Also, pravastatin significantly reduced the content of TCH in the blood and cartilage of the PEE offspring and improved cholesterol efflux pathway. Our in vitro findings further confirmed that pravastatin partially reversed cholesterol-induced inflammation and apoptosis of chondrocytes. In conclusion, pravastatin effectively reduced inflammation and matrix degradation, and thus ameliorate OA susceptibility in articular cartilage by relieving cholesterol accumulation in chondrocyte.
Pravastatin alleviates interleukin 1β-induced cartilage degradation by restoring impaired autophagy associated with MAPK pathway inhibition
2018, International Immunopharmacology
Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation driven by proinflammatory cytokines; meanwhile, statins display anti-inflammatory effects. Here we assessed the effects of pravastatin on inflammatory rat chondrocytes and explored the underlying mechanism.
Rat articular chondrocytes were pretreated with pravastatin and subsequently stimulated with IL1β. Then, the expression levels of OA- and autophagy-related effectors, at the mRNA and protein levels, were examined by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. Autophagic flux in chondrocytes in different treatment groups was monitored via GFP-mRFP-LC3 adenovirus transfection and confocal microscopy. Activation of MAPK, PI3K/Akt, and NF-κB pathways in chondrocytes with or without pravastatin treatment during IL1β stimulation was examined by Western blotting.
Our results showed that pravastatin downregulated the degradation related genes MMP3, MMP13 and ADAMTS5, as well as extracellular matrix degeneration induced by IL1β. In addition, pravastatin upregulated the autophagy related genes atg7, atg12, Beclin1, and LC3 II in IL1β stimulated chondrocytes. GFP-mRFP-LC3 adenovirus transfection also indicated that pravastatin restored impaired autophagy in OA chondrocytes. Furthermore, we demonstrated that regulation of the MAPK signaling pathway may be responsible for autophagy regulation in the articular cartilage.
Taken together, these findings suggested that pravastatin restores impaired autophagic flux by inhibiting MAPK activation and protects the cartilage against inflammatory responses, suggesting a potential role for autophagic flux in pravastatin-mediated cartilage protection.
Association between statin use and consultation or surgery for osteoarthritis of the hip or knee: a pooled analysis of four cohort studies
2017, Osteoarthritis and Cartilage
Citation Excerpt :
A reduction by statins of OA development has been reported in animal models of induced OA5,9–11 but was not confirmed in a spontaneous model12. With an appreciation that OA is partially driven by inflammation, relief of OA symptoms and development by statin use has been suggested5,13,14. Moreover, since there exist associations between OA and cardiovascular disease15, the effect of statins on OA could also be mediated indirectly by preventing atherosclerosis development.
Experimental findings and previous observational data have suggested lower risk of osteoarthritis (OA) with statin use but results are inconsistent. Large-scale studies with a clinically important outcome are needed. Thus, we aimed to determine whether statin use is associated with a reduced risk of developing clinically-defined hip or knee OA.
Pooled analysis based on time-to-event analysis of four population-based large cohorts, encompassing in total 132,607 persons aged 57–91 years resident in southern and central Sweden. We studied the association between statin use and time to consultation or surgery for OA of the hip or knee by time-dependent exposure analysis and Cox regression.
During 7.5 years of follow-up, we identified 7468 out- or inpatient treated cases of hip or knee OA. Compared with never use, current use of statins conferred no overall reduction in the risk of OA with an adjusted pooled hazard ratio (HR) of 1.04 (95% confidence intervals [95% CI] 0.99–1.10). We found no dose–response relation between duration of current statin use and the risk of OA, with similar HRs among patients with less than 1 year of use (HR 1.09; 95% CI 0.92–1.32) as in patients with use for 3 years or more (HR 1.05; 0.93–1.16). Results were comparable in those with low, medium and high dose of current statin use, without indications of heterogeneity of study results.
Statin use is not associated with reduced risk of consultation or surgery for OA of the hip or knee.
Assessment of subclinical carotid atherosclerosis in patients with primary osteoarthritis: Correlation with disease severity and insulin resistance
2014, Egyptian Rheumatologist
Citation Excerpt :
Osteoarthritis (OA) is the most common joint disease for middle aged and older people. It is characterized by joint pain and dysfunction [1]. Known risk factors for OA are age, female gender, and obesity [2].
To assess the carotid artery intima–media thickness (IMT) as an index of subclinical atherosclerosis in patients with primary osteoarthritis (OA) and its correlation to severity and insulin resistance (IR).
This study included 40 primary OA patients (28 with predominant knee OA and 12 with hip OA) and 15 age and sex matched controls. They were subjected to full medical history, thorough clinical examination and radiological assessment by plain X-rays of knee and hip joints scored according to the Kellgren–Lawrence grading. In patients and control, the IR was calculated by the homeostasis model assessment (HOMA) and carotid IMT measured by ultrasonography.
There was significant increased carotid IMT in OA patients (0.82 ± 0.12 mm) compared to controls (0.61 ± 0.02 mm) (p < 0.001) with cut-off value of 0.65 mm. There was significant higher HOMA in OA patients (2.55 ± 0.8) compared to controls (1.79 ± 0.44) (p < 0.001). OA patients with IMT > 0.65 mm (n = 34) had longer duration (9 ± 2.56y), higher Kellgren–Lawrence score (2.89 ± 0.45) and higher HOMA (3.8 ± 0.53) compared to those patients with IMT < 0.65 mm (n = 6) (3.41 ± 2.09 y, 2.01 ± 0.26 and 2.23 ± 0.32 respectively). Multi-regression analysis showed that disease duration, Kellgren–Lawrence Grading and HOMA are the best sensitive discriminators for patients having carotid intima >0.65 mm. (F ratio 36.54, p < 0.001).
Osteoarthritis patients have higher risk of subclinical atherosclerosis independent of traditional risk factors. The severity of OA may contribute to the progression of atherosclerotic disease. Measurement of insulin resistance in OA patients can identify those with higher risk of subclinical atherosclerosis and may help in their follow up and early intervention.

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The matrix metalloproteinases as pharmacological target in osteoarthritis: Statins may be of therapeutic benefit

Summary

Introduction

Section snippets

Cartilage degeneration in osteoarthritis

MMPs in osteoarthritis

Statins inhibit MMPs secretion

Can statins be used to treat osteoarthritis?

Conclusion

Semin Arthritis Rheu

Osteoarthritis Res Soc

Semin Arthritis Rheu

J Lipid Res

Pharmacol Therapeut

J Pharmacol Sci

Lancet

Lessons learned from nine clinical trials of disease-modifying osteoarthritis drugs

Arthritis Rheum