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

Abstract

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.

Benefits of Applying Nanotechnologies to Hydrogels in Efficacy Tests in Osteoarthritis Models—A Systematic Review of Preclinical Studies

“…Moreover, even NPs distribution, accumulation, degradation rates, and toxicokinetic profiles are gender-related [ 59 , 60 ]. Some studies reported that male rats and mice show a higher OA incidence and severity compared to females, both in spontaneous and surgically induced OA models [ 61 , 62 , 63 ]. Indeed, chemically induced OA female rats exhibit a greater vulnerability to chronic pain than males [ 64 ].…”

Rodent models of knee osteoarthritis for pain research

“…The DMM induced instability leads to cartilage degradation from 2 weeks post-surgery and progressively expands to subchondral bone sclerosis and osteophyte formation 63,64 . Asymmetric weight-bearing has been reported to occur from 8 65 , to 12 weeks post-surgery, which is reversed by celecoxib and morphine 63 . In a further study, mice developed secondary mechanical hypersensitivity (von Frey) from 4 weeks, maintained up to 16 weeks (Fig.…”

“…Partial MNX is achieved by unilaterally cutting the medial meniscus. In mice, this model leads to osteoarthritic changes 4 weeks post-surgery, increased mechanical sensitivity from 8 weeks post-surgery measured by von Frey filaments 78 , and altered weight-bearing from 7 weeks 65,79 . Partial MNX has been recently used in a proof of concept study where immunisation targeting NGF reduced asymmetric weight-bearing in mice 79 .…”

“…In contrast, orchiectomized males, the surgical removal of the testes, developed less severe OA than unoperated males 120 . Recent comparison studies using the DMM and partial meniscectomy surgical models in mice have shown that both males and females develop OA pain (secondary hyperalgesia and weight-bearing asymmetry) 65,121 . However, the damage in the knees of females (OARSI score 123 ) was less severe compared to males by week 12 [Fig.…”

“…However, the damage in the knees of females (OARSI score 123 ) was less severe compared to males by week 12 [Fig. 2(C)] 65 and by week 20 121 . Further investigation revealed this is not due to altered activity or repair differences as previously suggested 120 , but likely a heightened pain sensitivity by females that deters joint overuse.…”