Rodent models of knee osteoarthritis for pain research

Alves-Simões, Marta

doi:10.1016/j.joca.2022.01.010

Cited by 17 publications

(21 citation statements)

References 140 publications

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“…Most experimental animal studies of OA use surgical or chemical methods to cause OA in young animals (reviewed in (31)). These models offer many benefits, including controlling variability and low cost, but they may not precisely represent the pathological mechanisms involved in OA associated with aging.…”

Section: Introductionmentioning

confidence: 99%

Age-associated changes in knee osteoarthritis, pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice

Geraghty

Obeidat

Ishihara

et al. 2022

Preprint

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Objective: Osteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. While injury-induced OA models are useful, only a subset of OA is linked to traumatic injury. Here, we aimed to characterize age-associated joint damage, mechanical sensitization, and dorsal root ganglia (DRG) immune phenotypes in mice of both sexes. Methods: Male or female mice aged 6- or 20-months old were evaluated for histopathologic knee OA, pain-related behaviors, and L3-L5 dorsal root ganglia (DRG) immune characterization via flow cytometry. DRG gene expression in aged mice and humans was also examined. Results: Twenty-month old male mice had worse cartilage degeneration than 6-month old mice. Older female knees showed increased cartilage degeneration, but to a lesser degree than males. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells, and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male DRGs showed increased expression of Ccl2 and Ccl5 and older female DRGs showed increased Cxcr4 and Ccl3 compared to 6-month DRGs, among other differentially expresssed genes. Human DRG analysis from six individuals >80 years old revealed elevated CCL2 in male DRGs compared to females, whereas CCL3 was higher in female DRGs. Conclusions: Here we show that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of analgesic therapies.

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Section: Introductionmentioning

confidence: 99%

Age-associated changes in knee osteoarthritis, pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice

Geraghty

Obeidat

Ishihara

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…The majority of these preclinical studies used rodents as model organisms and mimicked mechanical loading/trauma (surgical models such as the DMM model), inflammation (such as the antigen-induced arthritis models) or genetically susceptible joint degeneration (the STR/Ort model). 154 As discussed in the previous sections, the converse is also true, with several inhibitors showing efficacy in animal models being terminated because of a lack of efficacy in clinical trials. Rodents differ from humans in articular cartilage physiology, weight bearing, gait, and sexdependent responses to catabolic stimuli and pain.…”

Section: Discussionmentioning

confidence: 99%

“…As discussed in the previous sections, the converse is also true, with several inhibitors showing efficacy in animal models being terminated because of a lack of efficacy in clinical trials. Rodents differ from humans in articular cartilage physiology, weight bearing, gait, and sex-dependent responses to catabolic stimuli and pain . Developing animal models able to capture more closely the complexity of human OA will help focusing drug development efforts on bona fide DMOAD candidates.…”

Section: Discussionmentioning

confidence: 99%

“…The development of many aggrecanase inhibitors was terminated owing to a lack of efficacy in animal models, which incompletely recapitulate human OA and are therefore poorly predictive of its progression. The majority of these preclinical studies used rodents as model organisms and mimicked mechanical loading/trauma (surgical models such as the DMM model), inflammation (such as the antigen-induced arthritis models) or genetically susceptible joint degeneration (the STR/Ort model) . As discussed in the previous sections, the converse is also true, with several inhibitors showing efficacy in animal models being terminated because of a lack of efficacy in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…Rodents differ from humans in articular cartilage physiology, weight bearing, gait, and sex-dependent responses to catabolic stimuli and pain. 154 Developing animal models able to capture more closely the complexity of human OA will help focusing drug development efforts on bona fide DMOAD candidates. Another factor that may affect the outcome of clinical trials is the choice of primary end point for the study.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition

et al. 2022

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Osteoarthritis (OA) is the most common degenerative joint disease. In 1999, two members of the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family of metalloproteinases, ADAMTS4 and ADAMTS5, or aggrecanases, were identified as the enzymes responsible for aggrecan degradation in cartilage. The first aggrecanase inhibitors targeted the active site by chelation of the catalytic zinc ion. Due to the generally disappointing performance of zinc-chelating inhibitors in preclinical and clinical studies, inhibition strategies tried to move away from the active-site zinc in order to improve selectivity. Exosite inhibitors bind to proteoglycan-binding residues present on the aggrecanase ancillary domains (called exosites). While exosite inhibitors are generally more selective than zinc-chelating inhibitors, they are still far from fulfilling their potential, partly due to a lack of structural and functional data on aggrecanase exosites. Filling this gap will inform the design of novel potent, selective aggrecanase inhibitors.

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Age‐Associated Changes in Knee Osteoarthritis, Pain‐Related Behaviors, and Dorsal Root Ganglia Immunophenotyping of Male and Female Mice

Geraghty

Obeidat

Ishihara

et al. 2023

Arthritis & Rheumatology

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ObjectiveOsteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. We undertook this study to characterize age‐associated changes in knee OA, pain‐related behaviors, and dorsal root ganglion (DRG) molecular phenotypes in mice of both sexes.MethodsMale or female C57BL/6 mice 6 or 20 months of age were evaluated for histopathologic knee OA, pain‐related behaviors, and L3–L5 DRG immune characterization via flow cytometry. DRG gene expression in older mice and humans was also examined.ResultsMale mice at 20 months of age had worse cartilage degeneration than 6‐month‐old mice. Older female mouse knees showed increased cartilage degeneration but to a lesser degree than those of male mice. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male mouse DRGs showed increased expression of Ccl2 and Ccl5, and older female mouse DRGs showed increased Cxcr4 and Ccl3 expression compared to 6‐month‐old mouse DRGs, among other differentially expressed genes. Human DRG analysis from 6 individuals >80 years of age revealed elevated CCL2 in men compared to women, whereas CCL3 was higher in DRGs from women.ConclusionWe found that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of OA therapies.image

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Rodent models of knee osteoarthritis for pain research

Cited by 17 publications

References 140 publications

Age-associated changes in knee osteoarthritis, pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice

Age-associated changes in knee osteoarthritis, pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice

Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition

Age‐Associated Changes in Knee Osteoarthritis, Pain‐Related Behaviors, and Dorsal Root Ganglia Immunophenotyping of Male and Female Mice

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