ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization

Malfait, Anne‐Marie; Ritchie, Judith A.; Gil, A.S.; Austin, Jean-Sébastien; Hartke, James R.; Qin, Wenning; Tortorella, Micky D.; Mogil, Jeffrey S.

doi:10.1016/j.joca.2009.11.013

Cited by 113 publications

(132 citation statements)

References 44 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…We observed increased mRNA expression of ADAMTS-5, but not ADAMTS-4, in LiCl-treated chondrocytes. It has been reported that ablation of ADAMTS-5 protects cartilage from degeneration in animal models of OA [37][38][39]. Collectively, our data demonstrate that activation of β-catenin (via LiCl) leads to articular chondrocyte maturation and the OA phenotype in eight week old rats.…”

Section: Discussionsupporting

confidence: 66%

Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

Niu

Wang

Xinghong

et al. 2011

International Orthopaedics (SICOT)

View full text Add to dashboard Cite

Purpose The objective of this study was to determine the role of β-catenin in normal postnatal articular cartilage growth and degeneration. Methods We investigated β-catenin gene and protein expression in hip cartilage cells of normal Wistar rats at two, four, six and eight weeks of age by using reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Primary articular chondrocytes from eight week old rats were cultured and treated with LiCl for activation of β-catenin. Collagen X and matrix metalloproteinase 13 (MMP-13) were detected by quantitative RT-PCR and immunofluorescence. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and 5 were detected by quantitative RT-PCR, and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) was used for detecting cell apoptosis. Results The highest levels of β-catenin expressions were detected in two week old rats, after which a steady decline was observed over the remaining period of observation (p< 0.05). When primary articular chondrocytes from eight week old rats were treated with LiCl, β-catenin mRNA and protein were induced (p<0.05). Moreover, LiCl-activated β-catenin in chondrocytes was associated with significant concomitant increases in mRNA expression of collagen X and the MMP-13 encoding collagenase 3. Significantly increased mRNA expression of ADAMTS-5 was also seen in primary chondrocytes from eight week old rats after LiCl treatment (p<0.05). The effect was specific to ADAMTS-5 since ADAMTS-4, which has similar proteolytic activity but different aggrecanase activity, was unaffected. Finally, TUNEL staining revealed that LiCl-activated β-catenin signalling led to increased cell apoptotic events in chondrocytes (p<0.05). Conclusions Our findings suggest that normal spatiotemporal patterns and degrees of Wnt/β-catenin signalling are needed to maintain postnatal articular cartilage growth and function. In the early stages of cartilage development, activation of β-catenin signalling is necessary for articular cartilage growth, while in adult cartilage it leads to degeneration and osteoarthritic-like chondrocytes.

show abstract

Section: Discussionsupporting

confidence: 66%

Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

Niu

Wang

Xinghong

et al. 2011

International Orthopaedics (SICOT)

View full text Add to dashboard Cite

show abstract

“…To understand the biological role of MCP-1/CCR2 signaling in mediating pain-related behaviors, we compared mechanical allodynia and locomotive behaviors for 16 wk after DMM in wild-type vs. Ccr2-null mice. In wild-type mice, mechanical allodynia occurred in the operated hindpaw after DMM but not sham surgery, as we previously reported (17). This allodynia progressed up to 4 wk and was maintained at a constant level up to 16 wk after surgery; age-matched naïve and sham-operated mice did not develop mechanical allodynia (Fig.…”

Section: Wild-type Mice Develop Mechanical Allodynia and Decreases Insupporting

confidence: 74%

“…3A). We previously reported that morphine and, to a lesser extent, acetaminophen reversed this mechanical allodynia (17). During the second stage, beginning at 8 wk after DMM surgery, behaviors indicative of movement-provoked pain were observed.…”

Section: Wild-type Mice Develop Mechanical Allodynia and Decreases Inmentioning

confidence: 83%

See 1 more Smart Citation

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Miller

Tran

Das

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

238

281

View full text Add to dashboard Cite

Osteoarthritis is one of the leading causes of chronic pain, but almost nothing is known about the mechanisms and molecules that mediate osteoarthritis-associated joint pain. Consequently, treatment options remain inadequate and joint replacement is often inevitable. Here, we use a surgical mouse model that captures the long-term progression of knee osteoarthritis to longitudinally assess pain-related behaviors and concomitant changes in the innervating dorsal root ganglia (DRG). We demonstrate that monocyte chemoattractant protein (MCP)-1 (CCL2) and its high-affinity receptor, chemokine (C-C motif) receptor 2 (CCR2), are central to the development of pain associated with knee osteoarthritis. After destabilization of the medial meniscus, mice developed early-onset secondary mechanical allodynia that was maintained for 16 wk. MCP-1 and CCR2 mRNA, protein, and signaling activity were temporarily up-regulated in the innervating DRG at 8 wk after surgery. This result correlated with the presentation of movement-provoked pain behaviors, which were maintained up to 16 wk. Mice that lack Ccr2 also developed mechanical allodynia, but this started to resolve from 8 wk onwards. Despite severe allodynia and structural knee joint damage equal to wild-type mice, Ccr2-null mice did not develop movement-provoked pain behaviors at 8 wk. In wild-type mice, macrophages infiltrated the DRG by 8 wk and this was maintained through 16 wk after surgery. In contrast, macrophage infiltration was not observed in Ccr2-null mice. These observations suggest a key role for the MCP-1/CCR2 pathway in establishing osteoarthritis pain.O steoarthritis is the most common joint disorder and is one of the leading causes of chronic pain (1, 2). Osteoarthritis commonly affects knees, hips, and hands and is characterized by radiographic changes (primarily joint space narrowing, subchondral bone sclerosis, and osteophytes) accompanied by clinical symptoms, most prominently pain. Treatments that alter the progression of the structural damage in the joint are not yet available. Options for treating the pain include nonsteroidal anti-inflammatory drugs, steroids, and viscosupplementation, but analgesia is often inadequate, and uncontrolled pain is the number one reason why people with osteoarthritis undergo joint-replacement surgery (3). Despite the enormous health and economic burden of osteoarthritis and associated pain (4), very few studies have examined the molecular pathways that mediate osteoarthritis pain. As in all types of chronic pain, osteoarthritis pain is the dynamic result of a complex interaction between local tissue damage and inflammation, peripheral and central sensitization, and the brain (5-7). Joint pain associated with osteoarthritis, however, has unique clinical features that provide insight into the mechanisms that cause it. First, joint pain has a strong mechanical component: it is typically triggered by specific activities (for example, climbing stairs elicits knee pain) and is relieved by rest. As structural joint disease advance...

show abstract

“…All mice were on the C57Bl6 background and were bred in-house. The ts5 Ϫ/Ϫ line was established by deletion of exon 2, as described previously (32). The Cd44 Ϫ/Ϫ line was obtained from The Jackson Laboratory, and the Cd44 Ϫ/Ϫ /ts5 Ϫ/Ϫ double knock-out line was established from heterozygous breeding pairs.…”

Section: Methodsmentioning

confidence: 99%

Adamts5 Deletion Blocks Murine Dermal Repair through CD44-mediated Aggrecan Accumulation and Modulation of Transforming Growth Factor β1 (TGFβ1) Signaling

Velasco

DiPietro

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

ADAMTS5 has been implicated in the degradation of cartilage aggrecan in human osteoarthritis. Here, we describe a novel role for the enzyme in the regulation of TGF␤1 signaling in dermal fibroblasts both in vivo and in vitro. Dermal wound healing involves a series of cellular responses that depend on the coordinated temporal and spatial expression of inflammatory cytokines, proteases, growth factors, and extracellular matrix molecules. The early phases of hemostasis, inflammation, and re-epithelialization are followed by granulation tissue formation and finally dermal remodeling (1, 2). The granulation tissue is a loosely organized collagenous matrix that serves as a template for cellular regeneration (3) of the collagen (4) and proteoglycan (5-7) structures of the dermis proper.There has been a long held consensus that proteinases, such as plasmin and matrix metalloproteinases, are major players in dermal repair; however, many questions remain regarding substrate and product identification and to what extent cleavage of particular proteins is destructive or reparative (reviewed in Ref. 8). Although much interest has focused on matrix metalloproteinases (9), the ADAMTSs have now also been found to play a major role in a range of repair and regeneration processes. For example, evidence of a role for ADAMTS activity in dermal repair comes from the finding that human skin contains abundant aggrecanase-generated catabolic fragments of versican V0 and V1 (5) and that both aggrecan and versican are associated with the dermal region of the hair follicle (7). Moreover, to place dermal matrix turnover in a broader context, cleavage of the hyalectans aggrecan, versican, and brevican by one or more aggrecanases (ADAMTS1, -4, -5, -8, -9, and -15) occurs in the remodeling of cartilage (10), aorta (11, 12), spinal cord (13), meniscus (14, 15) intervertebral disc (16), adipose tissue (17), and brain (18). HA 2 in the skin is most abundant in the epidermal layer (6), and it undergoes partial fragmentation in both the dermis and epidermis of human skin explants (19). Its role in skin biology has largely focused on its binding to the cell-surface receptor CD44, an interaction that prevents PDGF-BB receptor activation and human fibroblast migration (20). It also appears to be required for MMP9-mediated activation of TGF␤1 (21). HA has been shown to ligate RHAMM to promote the association of CD44 and p-ERK, an interaction that directly activates cell migration and thereby is required for efficient dermal repair (22,23). HA also regulates the proliferative response of dermal fibroblasts to TGF␤1 (24), and HA12 oligosaccharides stimulate Col3 and TGF␤1 expression (25), a finding that is very relevant to the data described here.TGF␤1 is a key regulator of multiple processes in dermal wound healing (26). In the context of this study, TGF␤1 stimulates col1 and col3 production by fibroblasts and is required for terminal differentiation of myofibroblasts during wound * This work was supported, in whole or in part, by National Institutes o...

show abstract

ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization

Abstract: Joint pathology following DMM surgery in mice is associated with progressive mechanical allodynia. ADAMTS-5 null mice are resistant to DMM-induced OA-like lesions and to the associated mechanical allodynia.

Cited by 113 publications

References 44 publications

Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

Dual function of β-catenin in articular cartilage growth and degeneration at different stages of postnatal cartilage development

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Adamts5 Deletion Blocks Murine Dermal Repair through CD44-mediated Aggrecan Accumulation and Modulation of Transforming Growth Factor β1 (TGFβ1) Signaling

Contact Info

Product

Resources

About