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Updated: Mar 29, 2026
Assessment of Knee Hyperalgesia in Mice using Pressure Application Measurement
Published on: June 13, 2025
Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic
Clare Driscoll1, Anastasios Chanalaris1, Chancie Knights2
1Kennedy Institute of Rheumatology and University of Oxford, Oxford, UK.
Objective:
Pain 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.
Methods:
Ten-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.
Results:
Mice 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 β-activated kinase 1-, fibroblast growth factor 2-, and Src kinase-dependent manner.
Conclusion:
Damaged joint tissues produce proalgesic molecules, including NGF, in murine OA.
Insights
Osteoarthritis (OA) pain originates from damaged joint tissues producing proalgesic molecules like nerve growth factor (NGF). This study identified key pain-sensitizing molecules and their regulation in articular cartilage during OA development in mice.
Area of Science:
- Orthopedics
- Pain Research
- Molecular Biology
Background:
- Osteoarthritis (OA) is characterized by joint pain, but its molecular drivers within the joint remain unclear.
- Understanding the origin and mechanisms of OA pain is crucial for developing effective treatments.
Purpose of the Study:
- To identify pain-sensitizing molecules regulated in the joint during OA development in mice.
- To determine the specific tissues where these molecules are regulated.
- To investigate the factors controlling their regulation.
Main Methods:
- Surgical induction of OA in mice (partial meniscectomy, DMM) followed by behavioral pain assessment.
- Gene expression analysis (RT-PCR) of pain-related genes in whole joints and microdissected tissues (articular cartilage, meniscus, bone).
- In vitro cartilage injury assays and measurement of nerve growth factor (NGF) protein levels.
Main Results:
- Mice developed OA-related pain behavior post-surgery.
- Nerve growth factor (NGF), bradykinin receptors, and tachykinin/receptor 1 were significantly regulated in joints with pain.
- NGF and other pain sensitizers were primarily regulated in articular cartilage, with NGF and tachykinin induced by mechanical cartilage injury.
- Little regulation of inflammatory cytokines or chemokines was observed.
Conclusions:
- Damaged joint tissues, particularly articular cartilage, produce proalgesic molecules like NGF in OA.
- Mechanical injury to cartilage is a key factor in regulating these pain-sensitizing molecules.
