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The nociceptive innervation of the normal and osteoarthritic mouse knee.

ABSTRACT: OBJECTIVES:To document the nociceptive innervation of the normal and osteoarthritic murine knee. METHODS:Knees were collected from naïve male C57BL/6 NaV1.8-tdTomato reporter mice aged 10, 26, and 52 weeks (n = 5/group). Destabilization of the medial meniscus (DMM) or sham surgeries (n = 5/group) were performed in the right knee of 10-week old male NaV1.8-tdTomato mice, and knees were harvested 16 weeks later. Twenty 20-?m frozen sections from a 400-?m mid-joint region were collected for confocal microscopy. Integrated density of the tdTomato signal was calculated using Image J by two independent observers blinded to the groups. Consecutive sections were stained with hematoxylin & eosin. C57BL/6-Pirt-GCaMP3 mice (n = 5/group) and protein gene product 9.5 (PGP9.5) immunostaining of C57BL/6 wild type (WT) mice (n = 5/group) were used to confirm innervation patterns. RESULTS:In naive 10-week old mice, nociceptive innervation was most dense in bone marrow cavities, lateral synovium and at the insertions of the cruciate ligaments. By age 26 weeks, unoperated knees showed a marked decline in nociceptors in the lateral synovium and cruciate ligament insertions. No further decline was observed by age 1 year. Sixteen weeks after DMM, the medial compartment of OA knees exhibited striking changes in NaV1.8+ innervation, including increased innervation of the medial synovium and meniscus, and nociceptors in subchondral bone channels. All results were confirmed through quantification, also in Pirt-GCaMP3 and PGP9.5-immunostained WT mice. CONCLUSIONS:Nociceptive innervation of the mouse knee markedly declines by age 26 weeks, before onset of spontaneous OA. Late-stage surgically induced OA is associated with striking plasticity of joint afferents in the medial compartment of the knee.

SUBMITTER: Obeidat AM

PROVIDER: S-EPMC7020657 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The nociceptive innervation of the normal and osteoarthritic mouse knee.

Obeidat A M AM Miller R E RE Miller R J RJ Malfait A-M AM

Osteoarthritis and cartilage 20190725 11

<h4>Objectives</h4>To document the nociceptive innervation of the normal and osteoarthritic murine knee.<h4>Methods</h4>Knees were collected from naïve male C57BL/6 Na<sub>V</sub>1.8-tdTomato reporter mice aged 10, 26, and 52 weeks (n = 5/group). Destabilization of the medial meniscus (DMM) or sham surgeries (n = 5/group) were performed in the right knee of 10-week old male Na<sub>V</sub>1.8-tdTomato mice, and knees were harvested 16 weeks later. Twenty 20-μm frozen sections from a 400-μm mid-jo ...[more]

PMID: 31351964

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Project description:BACKGROUND:Gait analysis can be used to measure variations in joint function in patients with knee osteoarthritis (OA), and is useful when observing longitudinal biomechanical changes following Total Knee Replacement (TKR) surgery. The Cardiff Classifier is an objective classification tool applied previously to examine the extent of biomechanical recovery following TKR. In this study, it is further developed to reveal the salient features that contribute to recovery towards healthy function. METHODS:Gait analysis was performed on 30 patients before and after TKR surgery, and 30 healthy controls. Median TKR follow-up time was 13 months. The combined application of principal component analysis (PCA) and the Cardiff Classifier defined 18 biomechanical features that discriminated OA from healthy gait. Statistical analysis tested whether these features were affected by TKR surgery and, if so, whether they recovered to values found for the controls. RESULTS:The Cardiff Classifier successfully discriminated between OA and healthy gait in all 60 cases. Of the 18 discriminatory features, only six (33%) were significantly affected by surgery, including features in all three planes of the ground reaction force (p<0.001), ankle dorsiflexion moment (p<0.001), hip adduction moment (p = 0.003), and transverse hip angle (p = 0.007). All but two (89%) of these features remained significantly different to those of the control group after surgery. CONCLUSIONS:This approach was able to discriminate gait biomechanics associated with knee OA. The ground reaction force provided the strongest discriminatory features. Despite increased gait velocity and improvements in self-reported pain and function, which would normally be clinical indicators of recovery, the majority of features were not affected by TKR surgery. This TKR cohort retained pre-operative gait patterns; reduced sagittal hip and knee moments, decreased knee flexion, increased hip flexion, and reduced hip adduction. The changes that were associated with surgery were predominantly found at the ankle and hip, rather than at the knee.

Project description:ObjectivePain is the most common symptom of osteoarthritis (OA), yet where it originates in the joint and how it is driven are unknown. The aim of this study was to identify pain-sensitizing molecules that are regulated in the joint when mice subjected to surgical joint destabilization develop OA-related pain behavior, the tissues in which these molecules are being regulated, and the factors that control their regulation.MethodsTen-week-old mice underwent sham surgery, partial meniscectomy, or surgical destabilization of the medial meniscus (DMM). Pain-related behavior as determined by a variety of methods (testing of responses to von Frey filaments, cold plate testing for cold sensitivity, analgesiometry, incapacitance testing, and forced flexion testing) was assessed weekly. Once pain-related behavior was established, RNA was extracted from either whole joints or microdissected tissue samples (articular cartilage, meniscus, and bone). Reverse transcription-polymerase chain reaction analysis was performed to analyze the expression of 54 genes known to regulate pain sensitization. Cartilage injury assays were performed using avulsed immature hips from wild-type or genetically modified mice or by explanting articular cartilage from porcine joints preinjected with pharmacologic inhibitors. Levels of nerve growth factor (NGF) protein were measured by enzyme-linked immunosorbent assay.ResultsMice developed pain-related behavior 8 weeks after undergoing partial meniscectomy or 12 weeks after undergoing DMM. NGF, bradykinin receptors B1 and B2, tachykinin, and tachykinin receptor 1 were significantly regulated in the joints of mice displaying pain-related behavior. Little regulation of inflammatory cytokines, leukocyte activation markers, or chemokines was observed. When tissue samples from articular cartilage, meniscus, and bone were analyzed separately, NGF was consistently regulated in the articular cartilage. The other pain sensitizers were also largely regulated in the articular cartilage, although there were some differences between the 2 models. NGF and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a transforming growth factor ?-activated kinase 1-, fibroblast growth factor 2-, and Src kinase-dependent manner.ConclusionDamaged joint tissues produce proalgesic molecules, including NGF, in murine OA.

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The nociceptive innervation of the normal and osteoarthritic mouse knee.

Publications

The nociceptive innervation of the normal and osteoarthritic mouse knee.

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