High levels of synovial fluid osteoprotegerin (OPG) and increased serum ratio of receptor activator of nuclear factor-κB ligand (RANKL) to OPG correlate with disease severity in patients with primary knee osteoarthritis

Pilichou, Anastasia; Papassotiriou, Ioannis; Michalakakou, Kelly; Fessatou, Smaragdi; Fandridis, Emmanuel; Papachristou, G.; Terpos, Evangelos

doi:10.1016/j.clinbiochem.2008.02.011

Cited by 58 publications

(35 citation statements)

References 9 publications

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“…We observed an approximate 2-fold increase in the RANKL/OPG ratio using serum specimens from CHIKV patients. This is similar in magnitude to the increases in RANKL/OPG ratios reported for patients with postmenopausal osteoporosis (1.8-fold) (58), osteoarthritis patients (ϳ1.5-fold) (59), and children with osteoporosis due to glucocorticoid therapy for idiopathic nephrotic syndrome (ϳ1.5-fold) (60).…”

Section: Discussionsupporting

confidence: 69%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

109

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The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (CT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-B ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.

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Section: Discussionsupporting

confidence: 69%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

109

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“…Th is result is similar with those reported by Pilichou et al [8], who showed synovial osteoprotegerin levels four times higher than serum ones. Th erefore, synovial osteoprotegerin is involved in the pathology of knee osteoarthritis, suggesting along with osteocalcin the dynamism of subchondral bone remodelling.…”

Section: Discussionsupporting

confidence: 82%

“…Correlation of osteocalcin and osteoprotegerin with the radiographically assessed severity of osteoarthritis is still an issue, when trying to establish the role of these biomarkers in osteoarthritis activity [6,[8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Correlation of Serum and Synovial Osteocalcin, Osteoprotegerin and Tumor Necrosis Factor-Alpha with the Disease Severity Score in Knee Osteoarthritis

Csifo

Katona

Arseni

et al. 2014

Acta Medica Marisiensis

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Objectives: Study of circulating and synovial levels of osteocalcin, osteoprotegerin and tumor necrosis factor-alpha (TNF-) in patients with different stages of knee osteoarthritis and correlation analysis of these parameters with disease severity. Methods: We enrolled 20 patients with different stages of knee osteoarthritis. The IKDC score (International Knee Documentation Comittee, 2000) was determined for each patient. Based on these data patients were divided into two groups: group I (advanced osteoarthritis) and group II (early osteoarthritis). Serum and synovial fl uid levels of osteocalcin, osteoprotegerin, TNF- were determined. Results: For the entire group the level of osteocalcin in the serum showed higher values than in the synovial fl uid. We found statistically signifi cant differences in the serum levels of osteocalcin between the two groups (group I: 2.18 ± 0.54 ng/ml, group II: 6.07 ± 1.98 ng/ml, p = 0.019). Serum and synovial osteocalcin in the whole study lot could not be correlated with the disease score, however we observed a tendency towards signifi cant negative correlation between the serum osteocalcin and IKDC score for group I and between synovial osteocalcin and IKDC score in group II. In the entire group, synovial osteoprotegerin concentration was six times higher than the serum osteoprotegerin level (p <0.0001) and TNF- showed higher circulating levels than local concentrations. Conclusions: In the advanced osteoarthritis group the serum and synovial osteocalcin show lower values than in the early osteoarthritis group, which means that as the disease progresses, bone anabolism decreases. In the case of osteoprotegerin, no signifi cant difference between the two groups was detected.

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“…Other studies also suggested an imbalance between bone formation and bone resorption indices in OA patients and, more specifically, identified increases in OPG and soluble RANKL (sRANKL). These increases actually led to an increased sRANKL/OPG ratio, which should favour bone resorption in OA patients, and correlated with disease severity [120].…”

Section: Bone Markers In Oamentioning

confidence: 93%

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

Tat

Lajeunesse

Pelletier

et al. 2010

Best Practice & Research Clinical Rheumatology

157

121

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Over the past few decades, significant progress has been made with respect to new concepts about the pathogenesis of osteoarthritis (OA). This article summarises some of the knowledge we have today on the involvement of the subchondral bone in OA. It provides substantial evidence that changes in the metabolism of the subchondral bone are an integral part of the OA disease process and that these alterations are not merely secondary manifestations, but are part of a more active component of the disease. Thus, a strong rationale exists for therapeutic approaches that target subchondral bone resorption and/or formation, and data evaluating the drugs targeting bone remodelling raise the hope that new treatment options for OA may become available.

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High levels of synovial fluid osteoprotegerin (OPG) and increased serum ratio of receptor activator of nuclear factor-κB ligand (RANKL) to OPG correlate with disease severity in patients with primary knee osteoarthritis

Cited by 58 publications

References 9 publications

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Correlation of Serum and Synovial Osteocalcin, Osteoprotegerin and Tumor Necrosis Factor-Alpha with the Disease Severity Score in Knee Osteoarthritis

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

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