Studying Osteoarthritis Pathogenesis in Mice

Blease, Andrew; Borges, Patricia Das Neves; Curtinha, M.; Javaheri, Behzâd; Loga, Isabell S. von; Parisi, Ida; Zarebska, J; Pitsillides, Andrew A.; Vincent, Tonia L.; Potter, Paul K.

doi:10.1002/cpmo.50

Cited by 9 publications

(5 citation statements)

References 45 publications

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“…Weight bearing measurement. Static weight bearing measurements were performed using a Linton Incapacitance Tester (Linton Instrumentation) as previously described (30,31). Briefly, mice were first acclimated to the chamber on 2 separate occasions over 2 weeks before experimental measurements.…”

Section: Methodsmentioning

confidence: 99%

Does Pain at an Earlier Stage of Chondropathy Protect Female Mice Against Structural Progression After Surgically Induced Osteoarthritis?

Loga

Batchelor

Driscoll

et al. 2020

Arthritis & Rheumatology

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Objective Female C57BL/6 mice exhibit less severe chondropathy than male mice. This study was undertaken to test the robustness of this observation and explore underlying mechanisms. Methods Osteoarthritis was induced in male and female C57BL/6 or DBA/1 mice (n = 6–15 per group) by destabilization of the medial meniscus (DMM) or partial meniscectomy (PMX). Some mice were ovariectomized (OVX) (n = 30). In vivo repair after focal cartilage defect or joint immobilization (sciatic neurectomy) following DMM was assessed. Histologic analysis, evaluation of gene expression in whole knees, and behavioral analysis using Laboratory Animal Behavior Observation Registration and Analysis System (LABORAS) and Linton incapacitance testing (n = 7–10 mice per group) were performed. Results Female mice displayed less severe chondropathy (20–75% reduction) across both strains and after both surgeries. Activity levels after PMX were similar for male and female mice. Some repair‐associated genes were increased in female mouse joints after surgery, but no repair differences were evident in vivo. Despite reduced chondropathy, female mice developed pain‐like behavior at the same time as male mice. At the time of established pain‐like behavior (10 weeks after PMX), pain‐associated genes were significantly up‐regulated in female mice, including Gdnf (mean ± SEM fold change 2.54 ± 0.30), Nrtn (6.71 ± 1.24), Ntf3 (1.92 ± 0.27), and Ntf5 (2.89 ± 0.48) (P < 0.01, P < 0.01, P < 0.05, and P < 0.001, respectively, versus male mice). Inflammatory genes were not regulated in painful joints in mice of either sex. Conclusion We confirm strong structural joint protection in female mice that is not due to activity or intrinsic repair differences. Female mice develop pain at the same time as males, but induce a distinct set of neurotrophins. We speculate that heightened pain sensitivity in female mice protects the joint by preventing overuse.

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Section: Methodsmentioning

confidence: 99%

Does Pain at an Earlier Stage of Chondropathy Protect Female Mice Against Structural Progression After Surgically Induced Osteoarthritis?

Loga

Batchelor

Driscoll

et al. 2020

Arthritis & Rheumatology

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“…Knee joints were imaged using a micro‐CT scanner (SkyScan 1172 X‐ray microtomograph, Bruker microCT, Kontich, Belgium) within 70% ethanol (10 μm/pixel, 3 minutes of acquisition time). ( 45 ) Using the CTan (Bruker) program, saved image sequences were opened in the software to conduct 3D parameter analysis. Regions of interest including the epiphysis and the bone directly underneath the epiphyseal plate were defined and used to calculate the bone volume (BV), total volume (TV), and ratio of BV to TV (BV/TV).…”

Section: Methodsmentioning

confidence: 99%

Ciliary IFT88 Protects Coordinated Adolescent Growth Plate Ossification From Disruptive Physiological Mechanical Forces

Coveney

Samvelyan

Miotla‐Zarebska

et al. 2020

Journal of Bone and Mineral Research

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Compared with our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programs, including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule-based organelles tuning a range of cell activities, including signaling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88 fl/fl ) in the juvenile and adolescent skeleton using a cartilage-specific, inducible Cre (AggrecanCreER T2 Ift88 fl/fl ). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption, and mineralization. These effects were largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. Although normal patterns of hedgehog signaling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity, and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilization inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano-dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces.

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“…Firstly, the eventual need to cull excessively grooming animals around 18 weeks of age greatly limited the breeding capacity of the DKO colony and thus the ability to increase the size of the colony. Secondly, DMM surgery is typically performed on mice aged 10 to 12 weeks of age with harvesting of legs for histological analysis at 6 to 10 weeks post-surgery (Blease et al, 2018). Therefore, because of the excessive grooming phenotype, animals were unlikely to survive the full length of the DMM experiment before needing to be culled.…”

Section: Analysis Of Growth Platesmentioning

confidence: 99%