Modeling and Staging of Osteoarthritis Progression Using Serial CT Imaging and Arthroscopy

Flynn, Candace; Hurtig, Mark; Lamoure, Emma; Cummins, Erin; Roati, Valeria; Lowerison, Mark; Jeong, Sang Young; Oh, Wonil; Linden, Alex zur

doi:10.1177/1947603518789997

Cited by 5 publications

(5 citation statements)

References 42 publications

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“…5C). Changes in knee joint shape, which can be used as a biomarker of OA in people ( 35 ) and animals ( 36 ), were also limited in dogs receiving R805 (Fig. 5D).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis

et al. 2023

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Adult mammals are incapable of multitissue regeneration, and augmentation of this potential may shift current therapeutic paradigms. We found that a common co-receptor of interleukin 6 (IL-6) cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) were resistant to surgically induced osteoarthritis as reflected by reduced loss of proteoglycans, reduced synovitis, and synovial fibrosis. The F814 mice also exhibited enhanced regenerative, not reparative, responses after wounding in the skin. In addition, pharmacological modulation of gp130 Y814 upstream of the SRC and MAPK circuit by a small molecule, R805, elicited a protective effect on tissues after injury. Topical administration of R805 on mouse skin wounds resulted in enhanced hair follicle neogenesis and dermal regeneration. Intra-articular administration of R805 to rats after medial meniscal tear and to canines after arthroscopic meniscal release markedly mitigated the appearance of osteoarthritis. Single-cell sequencing data demonstrated that genetic and pharmacological modulation of Y814 resulted in attenuation of inflammatory gene signature as visualized by the anti-inflammatory macrophage and nonpathological fibroblast subpopulations in the skin and joint tissue after injury. Together, our study characterized a molecular mechanism that, if manipulated, enhances the intrinsic regenerative capacity of tissues through suppression of a proinflammatory milieu and prevents pathological outcomes in injury and disease.

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“…5C). Changes in knee joint shape, which can be used as a biomarker of OA in people ( 35 ) and animals ( 36 ), were also limited in dogs receiving R805 (Fig. 5D).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis

et al. 2023

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“…5C). Knee joint shape change, a validated imaging biomarker of OA in people (53) and animals (54) was also clearly controlled in dogs receiving IA R805 (Fig.…”

Section: R805 Demonstrates Disease Modifying Effects In Small and Large Animal Models Of Osteoarthritismentioning

confidence: 90%

Signaling modality within gp130 receptor enhances tissue regeneration

Shkhyan

Flynn

Lamoure

et al. 2022

Preprint

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Adult mammals are incapable of multi-tissue regeneration and augmentation of this potential may drastically shift current therapeutic paradigms. Here, we found that a common co-receptor of IL-6 cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) exhibit regenerative, not reparative, responses after wounding in skin and anti-degenerative responses in the synovial joint. In addition, pharmacological inhibition of gp130 Y814 results in regeneration of multiple tissues in several species as well as disease modification in animal models of osteoarthritis. Our study characterizes a novel molecular mechanism that, if selectively manipulated, enhances the intrinsic regenerative capacity while preventing pathological outcomes in injury and disease.

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“…Since Gibbon first described cardiac surgery using cardiopulmonary bypass more than a half century ago [12], it is no overstatement to say that the history of cardiac surgery is the history of cardiopulmonary bypass development. Large animal models such as sheep and baboons have been used for the development of cardiopulmonary bypass and perioperative management, including anesthesia management models [13][14][15][16][17]. In the recent development of left ventricular assist devices (LVADs) for severe heart failure, large animal models such as bovine, dog, goat, pig, and sheep have been used.…”

Section: Advantages Of Large Animal Models For Cardiovascular Researc...mentioning

confidence: 99%

Large Animal Models in Cardiovascular Research

Osada¹,

Murata²,

Masumoto³

2023

Animal Models and Experimental Research in Medicine

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Studies of not only preclinical cardiovascular research but also those of life science, medical, and pharmacological fields commonly utilize small animal models. However, for the advancement of cardiovascular medicine, researches using large animal models are important step for preclinical validation of therapeutic efficacy and safety by virtue of having models with a body and heart size comparable with that of a human, providing clinically relevant experiments without the concern of over- or under-estimating therapeutic effects and risks. In particular, pigs are considered as a suitable animal model for research in cardiovascular medicine because of the similarities in physiology, metabolism, genomics, and proteomics to those in humans. Another advantage of pigs is the availability of various heart disease models such as myocardial infarction and genetically established cardiomyopathy. The present review updates the contributions of large animal model-based research to the development of cardiovascular medicine, especially focusing on the utility of pig models.

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Modeling and Staging of Osteoarthritis Progression Using Serial CT Imaging and Arthroscopy

Cited by 5 publications

References 42 publications

Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis

Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis

Signaling modality within gp130 receptor enhances tissue regeneration

Large Animal Models in Cardiovascular Research

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