Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors

Janusz, Michael J.; Hookfin, E.B.; Heitmeyer, S.A.; Woessner, Jeff; Freemont, Anthony J.; Hoyland, Judith A.; Brown, Kimberly K.; Hsieh, Lily C.; Almstead, Neil G.; De, Biswanath; Natchus, Michael G.; Pikul, S.; Taiwo, Yetunde O.

doi:10.1053/joca.2001.0472

Cited by 177 publications

(182 citation statements)

References 38 publications

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“…Joint pain is a cardinal sign of human OA, and reduction in pain along with prevention of further tissue damage and maintaining function are principal treatment goals. Evaluation of several broadspectrum inhibitors (PGE-621143, PGE-3162689, and PGE-6912923) in the MIA model showed chondroprotection (36-42% inhibition) comparable with that obtained with ALS 1-0635 (36).…”

Section: Discussionsupporting

confidence: 55%

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

150

127

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Objective. Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Methods. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.Results. A number of non-hydroxamic acidcontaining compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompeti-

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Section: Discussionsupporting

confidence: 55%

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Baragi

Becher²,

Bendele³

et al. 2009

Arthritis & Rheumatism

150

127

View full text Add to dashboard Cite

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“…These chondrocytes have similar histopathology to that of human OA and the MIA induced OA animal model closely mimics both the pain and structural changes associated with the disease (Janusz et al, 2001;Bove et al, 2003).…”

Section: Introductionmentioning

confidence: 78%

Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis

et al. 2011

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Abbreviations: GSPE, grape seed proanthocyanidin extract; MIA, monosodium iodoacetate; MMP, matrix metalloproteinase; O2 -, superoxide anion; OA, osteoarthritis; OH, hydroxyl radicals; ONOO -, peroxynitrite; PWL, paw withdrawal latency; PWT, paw withdrawal threshold; ROS, reactive oxygen species; TRP, transient receptor potential; VIP, vasoactive intestinal peptide Abstract Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P ＜ 0.05). GSPE reduced the loss of chondrocytes and proteoglycan, the production of MMP13, nitrotyrosine and IL-1β and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA.

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“…There are many experimental animal models of OA in humans including spontaneous models in both guineapig (22,23) and mouse (24); models of surgically-induced OA in dogs (25), rabbits (26) and guinea pigs (27,28); and models of OA induced by intraarticular injection of collagenase (29), IL-1 (30), or MIA (17,18), and so on. An MIA-induced rat model was selected in the present study because it can be used to evaluate clinical symptoms (31, 32), especially OA pain.…”

Section: Discussionmentioning

confidence: 99%

“…The vehicle control and AS1892802-treated groups consisted of 8 animals each. At the end of the study, the right knee was removed and carefully dissected to evaluate the severity of chondral alterations and the tibia was fixed in 10% formalin neutral buffered solution (Wako Pure Chemical, Osaka) (18). There were no signs of toxicity in any of the animals whether injected with vehicle or the compound.…”

Section: Induction Of Mia-induced Arthritismentioning

confidence: 99%

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

et al. 2011

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Abstract. The effects of AS1892802, a selective Rho-associated coiled coil kinase (ROCK) inhibitor, on knee cartilage damage and pain behavior were examined in a rat model of osteoarthritis (OA). Monoiodoacetate (MIA) was intraarticularly injected into the right knee joints of rats. ROCK I and II mRNA levels increased in knee joints of MIA-injected rats. Our newly synthesized ROCK inhibitor, AS1892802, was injected into the ipsilateral knee or administered p.o. for 3 weeks. The compound dose-dependently and significantly inhibited of cartilage damage in the tibial plateau in a dose-dependent manner and decreased the weight distribution deficit associated with MIA injection. In addition, the compound also inhibited bradykinin induced pain responses in normal rats. In vitro, the compound could induce chondrocyte differentiation in a chondrogenic cell line and significantly inhibited IL-1β-or bradykinin-induced prostaglandin E 2 production in a synovial cell line. AS1892802 prevents cartilage damage induced by MIA and has analgesic effects in rat pain models, suggesting that AS1892802 may be clinically useful for the treatment of OA.[Supplementary Figure: available only at http://dx

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Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors

Abstract: MMP inhibitors are partially protective against cartilage and subchondral bone damage induced by iodoacetate. These results support an important role for MMPs in mediating the joint damage in this model of arthritis.

Cited by 177 publications

References 38 publications

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models

Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis

Alleviating Effects of AS1892802, a Rho Kinase Inhibitor, on Osteoarthritic Disorders in Rodents

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