The inhibition of subchondral bone resorption in the early phase of experimental dog osteoarthritis by licofelone is associated with a reduction in the synthesis of MMP-13 and cathepsin K

Pelletier, Jean‐Pierre; Boileau, Christelle; Brunet, Julie; Boily, Mathieu; Lajeunesse, Daniel; Reboul, Pascal; Laufer, Stefan; Martel‐Pelletier, Johanne

doi:10.1016/j.bone.2003.11.021

Cited by 141 publications

(170 citation statements)

References 49 publications

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“…In a guinea pig model, bone densitometry evaluation following meniscectomy revealed typical variations in bone metabolism with early resorption of subchondral bone followed by increased bone density [18]. This concurs with findings from other animal models, such as the ACL dog and rat OA models, in which were observed, at an early stage of the disease process, increased subchondral bone resorption with trabecular thickness reduction and an increased number of osteoclasts, as well as increased production of catabolic factors including cathepsin K and matrix metalloproteinase (MMP)-13 [6][7][8][9].…”

Section: Correlation Between In Vivo Findings In Animals and Human Oasupporting

confidence: 83%

“…This protease has also been demonstrated to be involved in OA cartilage degradation and subchondral bone alterations [8,147]. Transgenic mouse models have provided evidence supporting its important role in arthritis.…”

Section: Drugs/agents That Target Bone Remodellingmentioning

confidence: 97%

“…Moreover, in this animal model, the severity of cartilage fibrillation and loss generally exceeds bone changes only in advanced OA. Although it has been shown in some induced OA animal models, which allow chronological analysis of the disease progression, that the subchondral bone changes precede cartilage changes [6][7][8][9], this has yet to be clarified in humans.…”

Section: Osteoarthritismentioning

confidence: 99%

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

Tat

Lajeunesse

Pelletier

et al. 2010

Best Practice & Research Clinical Rheumatology

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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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Section: Correlation Between In Vivo Findings In Animals and Human Oasupporting

confidence: 83%

Section: Drugs/agents That Target Bone Remodellingmentioning

confidence: 97%

Section: Osteoarthritismentioning

confidence: 99%

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

Tat

Lajeunesse

Pelletier

et al. 2010

Best Practice & Research Clinical Rheumatology

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“…Previous studies have indicated an abnormal resorption process in the subchondral bone of patients with OA (19,20), thus indicating alterations in osteoblast metabolism in this tissue as a possible target in the development of specific therapeutic strategies. In this context, we explored the effects of EphB4 receptor activation by its endogenous ligand ephrin B2 on human OA subchondral bone osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Since that time, there has been substantial evidence that changes in the metabolism of bone, particularly in the area of the subchondral bone, are an integral part of the disease (12)(13)(14)(15)(16)(17)(18). Recent studies, however, point to the fact that the fate of articular cartilage is not determined exclusively by stiffening (sclerosis) of subchondral bone, but rather, by a remodeling of this tissue (19,20). Some clinical studies performed in OA patients have shown that the markers of bone resorption are increased early in the disease course (21,22), whereas subchondral bone sclerosis is a relatively late phenomenon.…”

mentioning

confidence: 99%

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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Spontaneous development of synovitis and cartilage degeneration in transgenic mice overexpressing cathepsin K

Morko¹,

Kiviranta²,

Joronen³

et al. 2005

Arthritis & Rheumatism

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Objective. Several recent studies have demonstrated that cathepsin K, a proteolytic enzyme capable of degrading native fibrillar collagen, is overexpressed in osteoarthritic cartilage and inflamed synovial tissue. However, it is not known whether increased cathepsin K production is a primary or a secondary event in these diseases. The availability of transgenic UTU17 mice, which exhibit constitutive overexpression of the cathepsin K gene, prompted us to study possible arthritic changes in their knee joints.Methods. Progression of synovitis and articular cartilage degeneration in the knee joints of UTU17 mice and their nontransgenic littermates was monitored by histologic analyses at 7 and 12 months of age. Distribution of cathepsin K in the knee joints was studied by immunohistochemistry.Results. At the age of 7 months, UTU17 mice exhibited clear signs of synovitis, with strong immunostaining for cathepsin K in the synovial lining and the stroma, while control knee joints appeared normal. At 12 months, marked synovial thickening and fibrosis and severe degradation of cartilage and subchondral bone were observed in UTU17 mouse knee joints. In areas of cartilage degeneration, both chondrocytes and cells of hypertrophic synovia were positive for cathepsin K. At 12 months, synovia of control mice revealed only a few isolated cathepsin K-positive cells and mild changes in articular cartilage.Conclusion. Our findings demonstrate that overexpression of the cathepsin K gene under its own promoter in transgenic mice makes them susceptible to progressive synovitis, which, upon aging, results in synovial hyperplasia and fibrosis and subsequent destruction of articular cartilage and bone.

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The inhibition of subchondral bone resorption in the early phase of experimental dog osteoarthritis by licofelone is associated with a reduction in the synthesis of MMP-13 and cathepsin K

Cited by 141 publications

References 49 publications

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

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

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

Spontaneous development of synovitis and cartilage degeneration in transgenic mice overexpressing cathepsin K

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