Experimental models of osteoarthritis: A review

Troyer, Henry

doi:10.1016/0049-0172(82)90057-9

Cited by 38 publications

(15 citation statements)

References 79 publications

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“…z1lsao Imr obiliseaction timswee(as)g uan 21 Immobilisation time (days) Figure S Effects ofvarious combinations oftransforming growthfactor (TGF,B1) 0 5 nglml, transforming growthfactor,(2 (TGF(32) 0 5 ng/ml, and basic fibroblast growth factor (bFGF) 10 ng/ml on PG synthesis (measured as incorporation of35S-sulphate) in immobilised rabbit knee articular chondrocytes incubated in culture with the cytokines for seven days after isolation. Four kneesfor each time point; six dishes analysedfor each agent.…”

Section: Discussionmentioning

confidence: 99%

Effects of transforming growth factor beta s and basic fibroblast growth factor on articular chondrocytes obtained from immobilised rabbit knees.

Okazaki

Sakai

Nakamura

et al. 1996

Annals of the Rheumatic Diseases

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Objective-To clarify the effects of transforming growth factor ,1 (TGF(l1), TGF,32, and basic fibroblast growth factor (bFGF) on cell proliferation and proteoglycan (PG) 16 We have examined cartilage histologically and used a cell culture system of rabbit chondrocytes obtained from knee joints after immobilisation by fibreglass cast fixation for up to 42 days, in order to clarify whether there is a change in responsiveness of articular chondrocytes to TGFP1, TGF,B2, bFGF, and combinations thereof, during the development of OA. Materials and methods EXPERIMENTAL PROCEDUREThirty two male Japanese white rabbits, six months old and weighing approximately 3 kg, were used. A straight wooden splint measuring approximately 220 x 25 x 2 mm was applied to the dorsal aspect of the right leg from the proximal thigh to the distal end of the limb. The splint was tied to the limb by three to six turns of a fibreglass casting tape (Castlight; Alcare, Tokyo, Japan). The right knee joints of the rabbits were securely immobilised in full extension for periods ranging from 0 to 42 days. Six rabbits were used to examine histology; each was killed 0 (not fixed, day 0), four, seven, 14, 28, and 42 days after immobilisation. The other 26 animals were sacrificed 0, two, four, seven, 14, 28, and 42 days after immobilisation, for chondrocyte studies; two animals were killed at day 0 and four at each of the other time points.

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Section: Discussionmentioning

confidence: 99%

Effects of transforming growth factor beta s and basic fibroblast growth factor on articular chondrocytes obtained from immobilised rabbit knees.

Okazaki

Sakai

Nakamura

et al. 1996

Annals of the Rheumatic Diseases

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“…Full-length recombinant human proteins were used for MMPs 1, 2, 9, and 13. The catalytic domain of the protein was used for MMPs 3,7,8,10,12,14,15,16,20,24,25, and 26. PF152 potency was also evaluated using full-length bovine type II collagen by quantifying the generation of the one-quarter-length and threequarter-length fragments upon digestion with full-length human MMP-13 using sodium dodecyl sulfate-polyacrylamide gel electrophoresis.…”

Section: Methodsmentioning

confidence: 99%

Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in a dog model of osteoarthritis: Confirmation by multivariate analysis that modulation of type ii collagen and aggrecan degradation peptides parallels pathologic changes

Settle¹,

Vickery²,

Nemirovskiy³

et al. 2010

Arthritis & Rheumatism

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Objective. To demonstrate that the novel highly selective matrix metalloproteinase 13 (MMP-13) inhibitor PF152 reduces joint lesions in adult dogs with osteoarthritis (OA) and decreases biomarkers of cartilage degradation.Methods. The potency and selectivity of PF152 were evaluated in vitro using 16 MMPs, TACE, and ADAMTS-4 and ADAMTS-5, as well as ex vivo in human cartilage explants. In vivo effects were evaluated at 3 concentrations in mature beagles with partial medial meniscectomy. Gross and histologic changes in the femorotibial joints were evaluated using various measures of cartilage degeneration. Biomarkers of cartilage turnover were examined in serum, urine, or synovial fluid. Results were analyzed individually and in combination using multivariate analysis.Results. The potent and selective MMP-13 inhibitor PF152 decreased human cartilage degradation ex vivo in a dose-dependent manner. PF152 treatment of dogs with OA reduced cartilage lesions and decreased biomarkers of type II collagen (type II collagen neoepitope) and aggrecan (peptides ending in ARGN or AGEG) degradation. The dose required for significant inhibition varied with the measure used, but multivariate analysis of 6 gross and histologic measures indicated that all doses differed significantly from vehicle but not from each other. Combined analysis of cartilage degradation markers showed similar results.Conclusion. This highly selective MMP-13 inhibitor exhibits chondroprotective effects in mature animals. Biomarkers of cartilage degradation, when evaluated in combination, parallel the joint structural changes induced by the MMP-13 inhibitor. These data support the potential therapeutic value of selective MMP-13 inhibitors and the use of a set of appropriate biomarkers to predict efficacy in OA clinical trials.Osteoarthritis (OA) is a chronic degenerative joint disease affecting primarily aged or injured joints. The disease is characterized by an imbalance between cartilage synthesis and degradation, with increased breakdown of matrix components leading to proteoglycan loss and cartilage fibrillation, eventually resulting in severe cartilage defects. These changes are irreversible, and the only treatment other than palliative symptom control is total joint replacement. Therefore, the discovery of a disease-modifying osteoarthritis drug (DMOAD) would fill a large unmet medical need.

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“…Corticosteroid is also chondroprotective in this model (Pelletier & Martel-Pelletier, 1989), whereas indomethacin and salicylates are deleterious. Although animal models of OA may not be relevant to human OA (Troyer, 1982) they all tend to give broadly similar results for various putative CPAs (Burkhardt & Ghosh, 1987).…”

Section: Chondroprotective Agentmentioning

confidence: 99%

“…Animal models of OA may be of more value and a number have been used (Burkhardt & Ghosh, 1987;Troyer, 1982). For example various agents which may ameliorate or aggravate the OA process have been used in the Pond-Nuki dog model of OA which involves the response to anterior cruciate ligament section (Pond & Nuki, 1973).…”

Section: Chondroprotective Agentmentioning

confidence: 99%

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1992

Brit J Clinical Pharma

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Experimental models of osteoarthritis: A review

Cited by 38 publications

References 79 publications

Effects of transforming growth factor beta s and basic fibroblast growth factor on articular chondrocytes obtained from immobilised rabbit knees.

Effects of transforming growth factor beta s and basic fibroblast growth factor on articular chondrocytes obtained from immobilised rabbit knees.

Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in a dog model of osteoarthritis: Confirmation by multivariate analysis that modulation of type ii collagen and aggrecan degradation peptides parallels pathologic changes

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