Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients

Massicotte, Frédéric; Lajeunesse, Daniel; Benderdour, Mohamed; Pelletier, Jean Pierre; Hilal, George; Duval, Nicolas; Martel‐Pelletier, Johanne

doi:10.1053/joca.2002.0528

Cited by 164 publications

(182 citation statements)

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“…Cultures of subchondral bone osteoblasts were prepared as previously described (27). Briefly, bone samples were cut into small pieces and digested for 4 hours with type I collagenase in BGJ b medium (both from Sigma-Aldrich Canada, Oakville, Ontario, Canada), without serum, at a temperature of 37°C in a humidified atmosphere of 5% CO 2 /95% air.…”

Section: Methodsmentioning

confidence: 99%

“…Identification of human OA subchondral bone osteoblast subpopulations was performed as previously described (20,27,28). OA osteoblasts producing low levels of PGE 2 (Յ2,000 pg/mg of protein) were classified as L-OA, and those producing high levels of PGE 2 (Ͼ2,000 pg/mg of protein) as H-OA.…”

Section: Methodsmentioning

confidence: 99%

“…In previous studies, we showed that human OA subchondral bone osteoblasts could be discriminated into 2 subpopulations: low (L) and high (H) osteoblasts (27,28). L-OA osteoblasts showed bone proresorption activities, and H-OA osteoblasts showed proformation properties (20).…”

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confidence: 99%

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Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Tat¹,

Pelletier²,

Amiable³

et al. 2008

Arthritis & Rheumatism

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Objective. Abnormal subchondral bone metabolism is involved in osteoarthritis (OA). It has been suggested that ephrin B2 and its specific receptor EphB4 participate in bone homeostasis. We previously reported that human OA subchondral bone osteoblasts could be classified into 2 subpopulations: low (L), having proresorption properties, and high (H), having proformation properties. The purpose of this study was to investigate the importance of the ephrin system in OA subchondral bone osteoblasts.Methods. The presence of the EphB4 receptor was determined by immunohistochemistry, and its expression level, modulation upon treatment, and consequences of activation by ephrin B2 were determined by quantitative polymerase chain reaction. The effects of ephrin B2 activation of the EphB4 receptor on bone resorption activity were also determined. EphB4 receptor activation signaling pathways were investigated by specific enzyme-linked immunosorbent assay.Results. EphB4 receptors were present in subchondral bone osteoblasts and osteocytes. Compared with normal and H-OA osteoblasts, EphB4 receptor expression levels were significantly increased in L-OA osteoblasts, with no difference between normal and H-OA osteoblasts. EphB4 receptor levels in L-OA osteoblasts were significantly up-regulated by prostaglandin E 2 (PGE 2 ) and interleukin-17 (IL-17). Ephrin B2, PGE 2 , and IL-17 significantly inhibited bone resorption activity in these cells. EphB4 activation by ephrin B2 significantly inhibited the expression of IL-1␤, IL-6, matrix metalloproteinase 1 (MMP-1), MMP-9, MMP-13, and RANKL, but not MMP-2 and osteoprotegerin. EphB4 receptor activation significantly inhibited the phosphatidylinositol 3-kinase/Akt pathway.Conclusion. This study is the first to provide evidence that EphB4 receptor activation by ephrin B2 in OA subchondral bone could affect abnormal metabolism in this tissue by inhibiting resorption factors and their activities. Ephrin B2 could be targeted as a specific therapeutic approach in the development of a diseasemodifying OA drug.Subchondral bone is made up of a specialized connective tissue formed by a mineralized matrix containing the specific type I collagen, proteoglycans, and several growth factors and cytokines, as well as bonespecific cell types (osteoblasts, osteocytes, and osteoclasts) (1,2). Osteoblast and osteoclast activities, either alone or in combination, contribute to the bone remodeling process, and any disturbance in the activities of these 2 cells is responsible for the development of altered bone metabolism.The ephrin B molecules (ephrin B1, ephrin B2, and ephrin B3) bind in a specific manner to their EphB

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Tat¹,

Pelletier²,

Amiable³

et al. 2008

Arthritis & Rheumatism

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“…Lesional joint cartilage in the placebo-treated group exhibited morphologic changes, including cartilage fibrillation and fissures, changes in cellularity, such as cloning and hypocellularity, and loss of Safranin O staining, as previously described (11,20,21) (Figure 2). A decrease in the histologic score of the medial femoral condyles, indicative of a reduced severity of the lesions, was observed in dogs with OA treated with pioglitazone (median histologic score 6.25 [range [3][4][5][6][7][8][9][10][11][12] in the placebo group versus 4.25 [range [3][4][5][6][7] in the 15 mg/day pioglitazone group and 5.5 [range [5][6] in the 30 mg/day pioglitazone group); this difference was sig- nificant following a dosage of 15 mg/day pioglitazone as compared with the placebo group (P Ͻ 0.05). This reduction in histologic scores was mainly related to a protective effect of pioglitazone treatment on the severity of structural changes and the loss of Safranin O staining.…”

Section: Characteristics Of the Experimental Animalsmentioning

confidence: 99%

“…The subchondral bone remodeling that takes place during the evolution of OA is believed to be an important factor in cartilage degradation (2)(3)(4). Its contribution seems to be associated with both the abnormal biophysical properties of the tissue and the excess synthesis of many catabolic factors, including growth hormones and cytokines, that can modulate the metabolism of OA cartilage (5)(6)(7)(8).…”

mentioning

confidence: 99%

The peroxisome proliferator–activated receptor γ agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: In vivo protective effects mediated through the inhibition of key signaling and catabolic pathways

Boileau

Martel‐Pelletier

Fahmi

et al. 2007

Arthritis & Rheumatism

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Objective. Emerging evidence indicates that peroxisome proliferator-activated receptor ␥ (PPAR␥) may have protective effects in osteoarthritis (OA). The aim of this study was to evaluate the in vivo effect of a PPAR␥ agonist, pioglitazone, on the development of lesions in a canine model of OA, and to explore the influence of pioglitazone on the major signaling and metabolic pathways involved in OA pathophysiologic changes.Methods. OA was surgically induced in dogs by sectioning of the anterior cruciate ligament. The dogs were then randomly divided into 3 treatment groups in which they were administered either placebo, 15 mg/day pioglitazone, or 30 mg/day pioglitazone orally for 8 weeks. Following treatment, the severity of cartilage lesions was scored. Cartilage specimens were processed for histologic and immunohistochemical evaluations; specific antibodies were used to study the levels of matrix metalloproteinase 1 (MMP-1), ADAMTS-5, and inducible nitric oxide synthase (iNOS), as well as phosphorylated MAPKs ERK-1/2, p38, JNK, and NF-B p65.Results. Pioglitazone reduced the development of cartilage lesions in a dose-dependent manner, with the highest dosage producing a statistically significant change (P < 0.05). This decrease in lesions correlated with lower cartilage histologic scores. In addition, pioglitazone significantly reduced the synthesis of the key OA mediators MMP-1, ADAMTS-5, and iNOS and, at the same time, inhibited the activation of the signaling pathways for MAPKs ERK-1/2, p38, and NF-B.Conclusion. These results indicate the efficacy of pioglitazone in reducing cartilage lesions in vivo. The results also provide new and interesting insights into a therapeutic intervention for OA in which PPAR␥ activation can inhibit major signaling pathways of inflammation and reduce the synthesis of cartilage catabolic factors responsible for articular cartilage degradation.Osteoarthritis (OA), one of the most common arthritic conditions, is primarily related to the progressive erosion of articular cartilage associated with synovial inflammation. The changes in cartilage are linked to a combination of mechanical and biochemical factors (1). The subchondral bone remodeling that takes place during the evolution of OA is believed to be an important factor in cartilage degradation (2-4). Its contribution seems to be associated with both the abnormal biophysical properties of the tissue and the excess synthesis of many catabolic factors, including growth hormones and cytokines, that can modulate the metabolism of OA cartilage (5-8).

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New Drugs and Nutraceuticals in the Treatment of Osteoarthritis

Henrotin

Reginster

2011

Pharmaceutical Sciences Encyclopedia

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Osteoarthritis is a disease with a multifactorial etiology affecting all joint tissues and involving both biochemical and mechanical factors that act in synergy to degrade cartilage. Until now, OA treatments are limited to pain relief, even if some new drugs of the SYSADOA class have shown potential structure‐modifying effects. These drugs target cartilage as the endpoint of joint failure, underestimating the role played by subchondral bone and synovium in this process. However, recent studies emphasized the key role played by subchondral bone sclerosis and synovium inflammation in OA pathophysiology. Unfortunately, until now, there is no validated method for a reliable assessment of structural changes in these tissues, explaining that guidance documents edited by the official agencies and scientific societies are strictly focused on the assessment of cartilage changes.

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Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients

Abstract: These results indicate that IL-6 and PGE(2) production by subchondral Ob can discriminate two subgroups of osteoarthritic patients that cannot otherwise be separated by their expression of cell markers, and that endogenous PGE(2) levels influence IL-6 synthesis in osteoarthritic Ob.

Cited by 164 publications

References 44 publications

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts

The peroxisome proliferator–activated receptor γ agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: In vivo protective effects mediated through the inhibition of key signaling and catabolic pathways

New Drugs and Nutraceuticals in the Treatment of Osteoarthritis

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