ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro

Stanton, Heather; Rogerson, Fraser M.; East, Charlotte J.; Golub, Suzanne B.; Lawlor, Kate E.; Meeker, Clare T.; Little, Christopher B.; Farmer, Pamela J.; Campbell, Ian K.; Fourie, Anne M.; Fosang, Amanda J.

doi:10.1038/nature03417

Cited by 835 publications

(665 citation statements)

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“…ADAMTS-5 is 1 of 2 aggrecanase proteases that are members of the AD-AMTS family (31). ADAMTS-5 has been found at increased levels in OA cartilage (36). Moreover, a recent study of genetically modified mice in which the catalytic domain of ADAMTS-5 was deleted showed that after surgically induced joint instability, the course of cartilage destruction was abrogated (37).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Aggrecanase activity within the IGD is marked by scission of the NITEGE 392 -393 ARGSVI bond (Sandy, et al, 1991). ADAMTS-4 and -5 (aggrecanase-1 and -2, respectively) appear to mediate the bulk of destructive sGAG release from osteoarthritic human cartilage explants (Arner, et al, 1999), and ADAMTS-5 is primarily responsible for destructive aggrecanolysis in the mouse (Stanton, et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

et al. 2007

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Articular cartilage undergoes matrix degradation and loss of mechanical properties when stimulated with proinflammatory cytokines such as interleukin-1 (IL-1). Aggrecanases and matrix metalloproteinases (MMPs) are thought to be principal downstream effectors of cytokine-induced matrix catabolism, and aggrecanase-or MMP-selective inhibitors reduce or block matrix destruction in several model systems. The objective of this study was to use metalloproteinase inhibitors to perturb IL-1-induced matrix catabolism in bovine cartilage explants and examine their effects on changes in tissue compression and shear properties. Explanted tissue was stimulated with IL-1 for up to 24 days in the absence or presence of inhibitors which were aggrecanase-selective, MMP-selective, or non-selective. Analysis of conditioned media and explant digests revealed that aggrecanase-mediated aggrecanolysis was delayed to varying extents with all inhibitor treatments, but that aggrecan release persisted. Collagen degradation was abrogated by MMP-and non-selective inhibitors and reduced by the aggrecanase inhibitor. The inhibitors delayed but did not reduce loss of the equilibrium compression modulus, whereas the loss of dynamic compression and shear moduli was delayed and reduced. The data suggest that non-metalloproteinase mechanisms participate in IL-1-induced matrix degradation and loss of tissue material properties.

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“…In a model of inflammatory arthritis, ADAMTS-5, but not ADAMTS-4, knockout mice were protected against aggrecan loss (Stanton et al, 2005). Furthermore, aggrecanase activity was inducible in articular cartilage explants from wild-type and ADAMTS-4 knockout mice but not from ADAMTS-5 knockout littermates (Glasson et al, 2004(Glasson et al, , 2005Stanton et al, 2005). Together these studies suggest that, at least in these mouse models, ADAMTS-5 is primarily responsible for the increased aggrecanase activity and subsequent development of arthritis.…”

Section: Cartilage: Chondrocyte Apoptosis and Extracellular Matrix Dementioning

confidence: 85%

“…In a surgically induced OA model there was a major reduction in the severity of induced OA in ADAMTS-5 knockout mice, but no difference in progression or severity in ADAMTS-4 knockout mice (Glasson et al, 2004(Glasson et al, , 2005. In a model of inflammatory arthritis, ADAMTS-5, but not ADAMTS-4, knockout mice were protected against aggrecan loss (Stanton et al, 2005). Furthermore, aggrecanase activity was inducible in articular cartilage explants from wild-type and ADAMTS-4 knockout mice but not from ADAMTS-5 knockout littermates (Glasson et al, 2004(Glasson et al, , 2005Stanton et al, 2005).…”

Section: Cartilage: Chondrocyte Apoptosis and Extracellular Matrix Dementioning

confidence: 89%

“…Both ADAMTS-4 and -5 knockout mice were phenotypically normal and indistinguishable from wild-type littermates, indicating that each enzyme was dispensable for normal development (Glasson et al, 2004(Glasson et al, , 2005Stanton et al, 2005). In a surgically induced OA model there was a major reduction in the severity of induced OA in ADAMTS-5 knockout mice, but no difference in progression or severity in ADAMTS-4 knockout mice (Glasson et al, 2004(Glasson et al, , 2005.…”

Section: Cartilage: Chondrocyte Apoptosis and Extracellular Matrix Dementioning

confidence: 99%

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The role of proteases in pathologies of the synovial joint

Jones¹,

Riley²,

Buttle³

2008

The International Journal of Biochemistry & Cell Biology

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Synovial (diarthrodial) joints are employed within the body to provide skeletal mobility and have a characteristic structure adapted to provide a smooth almost frictionless surface for articulation. Pathologies of the synovial joint are an important cause of patient morbidity and can affect each of the constituent tissues. A common feature of these pathologies is degenerative changes in the structure of the tissue which is mediated, at least in part, by proteolytic activity. Most tissues of the synovial joint are composed primarily of extracellular matrix and key pathological roles in the degeneration of this matrix are performed by metalloproteinases such as matrix metallproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). However, other proteases such as cathepsin K are likely to play an important role, especially in bone turnover. In addition to the cleavage of structural proteins, proteolytic activities are employed to regulate the activity of other proteases, growth factors, cytokines and other inflammatory mediators. Proteases combine to form complex regulatory networks, the correct functioning of which is required for tissue homeostasis and the imbalance of which may be a feature of pathology. A precise understanding of the proteases involved in these networks is required for a true understanding of the associated pathology.

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ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro

Cited by 835 publications

References 24 publications

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

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

Selective and non-selective metalloproteinase inhibitors reduce IL-1-induced cartilage degradation and loss of mechanical properties

The role of proteases in pathologies of the synovial joint

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