Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis

Bove, Susan E.; Calcaterra, Salvatore; Brooker, Rachel M.; Huber, Colleen M.; Guzman, Roberto E.; Juneau, Paul; Schrier, Denis J.; Kilgore, Kenneth S.

doi:10.1016/s1063-4584(03)00163-8

Cited by 439 publications

(463 citation statements)

References 21 publications

(29 reference statements)

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“…The rat model of monoiodoacetate (MIA)-induced OA (23)(24)(25) was used for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. Male Sprague-Dawley rats weighing 175-200 gm (12 per group) were anesthetized for 1 minute in an inhalation chamber, using a mixture of carbon dioxide and oxygen (60:40), and on day 0 were injected in the right knee joint with 50 l saline containing 1 mg MIA.…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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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“…Animals were acclimatized to the laboratory room for at least 1 h before the start of each of the behavioural experiments. (Bove et al, 2003;Andrews et al, 2012).…”

Section: Animalsmentioning

confidence: 99%

Burrowing as a non‐reflex behavioural readout for analgesic action in a rat model of sub‐chronic knee joint inflammation

Rutten¹,

Schiene²,

Robens³

et al. 2013

European Journal of Pain

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Background: Innate responses against spontaneous pain are proposed to improve the predictive validity of preclinical analgesia models. Therefore, development and validation of novel readouts is necessary. To investigate whether innate rodent burrowing is a useful alternative behavioural readout for assessment of analgesic efficacy, a complete Freund's adjuvant (CFA)-induced model of sub-chronic inflammation was used to compare the effects of naproxen, ibuprofen and pregabalin in weight-bearing (WB), open-field (OF) and burrowing assays. Methods: Male Sprague Dawley rats were injected with 150 μL of CFA (2 mg/mL) into the knee (hind leg) 3 days before testing. Naproxen, ibuprofen and pregabalin were administered at different doses 30, 90 and 60 min, respectively, before testing. WB was determined using a rat incapacitance tester; horizontal distance moved and vertical rearings were recorded in an OF; and burrowing was measured by the weight of gravel remaining in a hollow tube after 60 min. Results: CFA-induced arthritis reduced WB, OF activity and burrowing. Naproxen, pregabalin and ibuprofen treatment normalized WB; however, horizontal OF activity was not improved by any treatment; rearing behaviour was moderately reinstated by ibuprofen (100 mg/kg). In burrowing, naproxen (100 mg/kg), ibuprofen (31.6 and 100 mg/kg) and pregabalin (10 mg/kg) reversed CFA-induced deficits. Conclusions: Burrowing performance is an alternative non-reflex readout relying on innate rodent behaviour that is affected by nociceptive behaviour and can be pharmacologically manipulated. The burrowing assay appears to be more sensitive than OF assays and is as sensitive as WB assays at distinguishing between analgesic doses and doses that impair locomotion.

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“…The dose of MIA used (1 mg/i.a. injection) was selected based on in-house efficacy data as well as from the literature [9,11].…”

Section: Induction Of Tibiofemoral Osteoarthritismentioning

confidence: 99%

“…administration of monosodium iodoacetate (MIA) in rats is a validated chemical model used to investigate OA. MIA, when injected through the patellar tendon in the hind limb of rodents, displays multiple components of disease progression and symptoms similar to human OA and induces significant nociceptive behavior [9][10][11] albeit with a different time course [12]. Alterations in hind limb weight bearing (WB) measured by an incapacitance test are widely used as a nociceptive behavioral outcome in the MIA model as the rat will carry less weight on a painful limb.…”

Section: Introductionmentioning

confidence: 99%

“…Alterations in hind limb weight bearing (WB) measured by an incapacitance test are widely used as a nociceptive behavioral outcome in the MIA model as the rat will carry less weight on a painful limb. This model evaluates static, resting nociceptive behavior by assessing WB alterations in a confined, immobilized position where the majority of the body weight is directed over the hind limbs [9,11], here defined as restricted WB. However, assessment of load bearing in an unrestricted and more natural position on all four limbs would be preferable.…”

Section: Introductionmentioning

confidence: 99%

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Unrestricted Weight Bearing as a Method for Assessment of Nociceptive Behavior in a Model of Tibiofemoral Osteoarthritis in Rats

Gregersen¹,

Røsland²,

Arendt-Nielsen³

et al. 2013

JBBS

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Background: Novel preclinical models for prediction of osteoarthritis-like pain are necessary for the elucidation of osteoarthritis (OA) pathology and for assessment of novel analgesics. A widely used behavioral test in rat models of tibiofemoral OA is hind limb weight bearing (WB). However, this method evaluates WB in an unnaturally restricted manner. The aim of this study was therefore to characterize the Tekscan Pressure Measurement System as a means to assess OA-like tibiofemoral pain in rats by determination of plantar pressure distribution in a more natural and unrestricted position, defined as unrestricted WB. Methods: Intra-articular injections of 1 mg monosodium iodoacetate (MIA) or saline were administrated in the left hind knee of 84 male Sprague Dawley rats. Changes in unrestricted WB between ipsilateral and contralateral hindlimbs were determined. Morphine (5 mg/kg administered subcutaneously) and naproxen (60 mg/kg per-oral) were examined for their ability to reverse WB changes. Results: Changes in hind limb unrestricted WB were observed 14 (P < 0.05), 21 (P < 0.001) and 28 (P < 0.001) days post intra-articular injections of MIA compared to control. These alterations were attenuated by morphine 1 hour post administration compared to baseline but were not affected by naproxen. Conclusion: This study indicated that unrestricted WB assessed by the Tekscan system can be utilized as a clinically relevant method to assess aberrations in WB induced by intra-articular MIA injections in rodents. Therefore, this system may be useful for understanding the mechanisms of OA pain in humans and may also assist in the discovery of novel pharmacological agents.

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Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis

Cited by 439 publications

References 21 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

Burrowing as a non‐reflex behavioural readout for analgesic action in a rat model of sub‐chronic knee joint inflammation

Unrestricted Weight Bearing as a Method for Assessment of Nociceptive Behavior in a Model of Tibiofemoral Osteoarthritis in Rats

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