Edition 10 - Pathophysiology of osteoarthritis: new insights

Research roundup

The aim of the research roundup is to provide vet professionals with an easy-to-read digest on items of research in pain management which focus on one common subject area.

This research roundups provide a single point of reference for the reader.

Subject

Pathophysiology of osteoarthritis

Title of the paper

Current understanding of osteoarthritis pathogenesis and relevant new approaches. Click here to access.

Aims of the paper

• Explore the molecular mechanisms of osteoarthritis (OA)

• Review epigenetic regulation in OA

• Summarise key mediators of OA-associated pain

• Introduce innovative research techniques

• Discuss cell death mechanisms in OA

• Highlight the role of the synovial lymphatic system

• Support development of targeted OA therapies

The key points are listed here and you can read more detail in the paper if you are interested in mechanisms. We focus on the pain mediators section.

Summary of the work

Understanding Osteoarthritis (OA): Challenges and New Directions

Overview: Osteoarthritis (OA) is the most common joint disease, causing chronic pain and disability. It affects over 300 million people globally, with no current cure or disease-modifying treatments—only symptom relief, often with side effects.

1. A Complex Disease Mechanism:

   • OA affects multiple joints (knee, hip, spine, TMJ).

   • Influenced by genetics, aging, obesity, injury, and more.

   • Involves cartilage damage, inflammation, bone remodeling, and pain.

2. Emerging Research Areas:

   • Epigenetics: Changes in DNA methylation, histone modification, and microRNAs affect gene expression in cartilage cells.

   • Pain Mediators: Molecules like NGF, CGRP, CCL2/CCR2, and TNFα are linked to OA pain.

   • Cell Death Pathways: New forms of regulated cell death (pyroptosis, ferroptosis, autophagy) are being studied for their roles in OA.

   • Synovial Lymphatics: The lymphatic system in joints may influence inflammation and disease progression.

3. Innovative Techniques:

   • Tools like CRISPR, single-cell RNA sequencing, and lineage tracing are helping uncover OA mechanisms and potential drug targets.

Let's look at the key players in pain processing.  

NGF and OA Pain: A Promising but Complex Target

What is NGF?

• Nerve Growth Factor (NGF) promotes nerve growth and is now known to be a key player in chronic pain, including OA-associated pain.

• It acts through its receptor TrkA, making the NGF/TrkA pathway a major target for pain relief.

Therapeutic Approaches:

1. Anti-NGF Antibodies:

   • Fasinumab and tanezumab are monoclonal antibodies targeting NGF in humans. In dogs we have bedinvetmab and cats, frunevetmab.

   • Clinical trials show significant pain relief in knee and hip OA patients in people.

   • However, some patients developed rapidly progressive OA, especially at higher doses.

2. TrkA Inhibitors:

   • Block NGF signaling at the receptor level.

   • Some local anaesthetics also inhibit TrkA.

Risks and Considerations:

• Rapidly progressive OA is a serious side effect observed in a small percentage of patients.

• The mechanism behind this adverse effect is not fully understood and requires further study.

NGF in other conditions:

• In facet joint (FJ) OA and low back pain (LBP), NGF is linked to:

  • Increased VEGF (an angiogenic factor)

  • Higher inflammatory cytokines

  • Greater nerve density in degenerative cartilage

• NGF is found mainly in damaged cartilage (80%) and bone marrow (20%) in FJ OA.

• Despite risks in knee OA, NGF inhibitors have shown strong efficacy in treating chronic LBP, especially when peripheral OA is not present.

Conclusion:

NGF is a powerful mediator of OA pain and a promising therapeutic target. However, its role in joint degeneration and the risk of rapid OA progression must be carefully managed in clinical applications.

CGRP in OA Pain: A Complex and Sex-Specific Pathway

What is CGRP?

• A neuropeptide found in unmyelinated C-fibres, involved in pain transmission, especially in migraine.

• Released from C-fibre terminals and sensitizes Aδ fibres, which express CGRP receptors (CLR and RAMP1).

Key Findings:

1. CGRP in Joint Pain:

   • Found in synovial tissue, a likely source of OA pain.

   • Intra-articular CGRP causes pain in animal models.

   • Blocking CGRP (via antibodies or receptor antagonists) reduces OA pain in animals.

2. Clinical Observations:

   • Serum CGRP levels and nerve fibre density correlate with OA pain severity in humans.

   • However, galcanezumab (a CGRP antibody) failed to relieve OA pain in a phase II trial.

3. Sex Differences in CGRP signaling:

   • Women with OA show higher CGRP and RAMP1 expression in synovium.

   • CGRP levels correlate with pain severity in females, but not in males.

   • Suggests sex-specific mechanisms in OA pain, warranting further research.

Conclusion:

CGRP is a key player in OA pain, especially in female patients, but its therapeutic targeting has shown mixed results. Understanding sex-specific pain pathways may improve treatment strategies.

CCL2/CCR2 Pathway: A Key Player in OA-Associated Pain

What is CCL2/CCR2?

• CCL2 (a chemokine) and its receptor CCR2 are involved in immune cell recruitment and pain signalling.

• They are active in dorsal root ganglia (DRG) and the spinal cord, key areas for pain processing.

Key Findings:

1. Pain Mediation in OA:

   • In OA mouse models, CCL2/CCR2 signalling contributes to pain behaviours.

   • This pathway activates nociceptors and promotes inflammation in joint tissues.

2. Experimental Evidence:

   • Mice lacking CCL2 or CCR2 show:

     • Reduced OA severity

     • Lower macrophage infiltration

     • Less joint inflammation

   • Blocking this pathway (e.g., with bindarit or RS-504393) improves synovitis and cartilage health.

3. Peripheral and Central Effects:

   • CCL2/CCR2 acts both:

     • Locally in the joint (promoting inflammation)

     • Centrally in the nervous system (enhancing pain sensitivity)

Conclusion:

The CCL2/CCR2 axis is a promising target for OA pain treatment. It influences both inflammatory responses and pain perception, making it a dual-action therapeutic candidate.

TNF-α: A Key Inflammatory Mediator in OA Pain

What is TNF-α?

• Tumour Necrosis Factor-alpha (TNF-α) is a major proinflammatory cytokine involved in joint damage and pain in OA.

• It is released by immune cells and acts on neurons, contributing to inflammatory and neuropathic pain.

Mechanisms of Action:

• TNF-α is released after joint damage and activates microglia and astrocytes, which then release:

  • Other cytokines (IL-1β, IL-6)

  • Chemokines (e.g., CCL2)

  • Excitatory neurotransmitters and nitric oxide

• These substances act on neurons in the spinal cord, enhancing pain by:

  • Increasing excitatory signals

  • Suppressing inhibitory signals

Clinical Trials and Challenges:

• Anti-TNF-α drugs like etanercept and adalimumab have not shown significant pain relief in hand OA clinical trials.

• Suggests that TNF-α inhibition alone may not be sufficient for OA pain management.

TNF Receptors:

• TNFR1: Found on most cells; promotes inflammation.

• TNFR2: Found on select cells (e.g., neurons, chondrocytes); inhibits inflammation and may be protective.

• Progranulin (PGRN)/TNFR2 signaling in chondrocytes has shown pain-relieving and cartilage-protective effects in OA models.

Conclusion:

While TNF-α is a central player in OA inflammation and pain, targeting TNFR2 (rather than TNF-α broadly) may offer a more effective and safer therapeutic strategy for OA-associated pain and joint protection.

The Zero Pain View

This paper helps us realise just how much more there is to understand with OA, beyond what we are commonly taught in the veterinary world. On this list of key pain players, we have just one option – which are the anti-NGF products. We can appreciate how many other potential targets there are and where future research directions lie. And also understand why we don’t currently have a full suite of solutions to control the pain of OA.

To read next

Osteoarthritis: New Insight on Its Pathophysiology. Click here to open the link.

Aims & key results

This review explores recent advancements in understanding the pathogenesis of osteoarthritis (OA). Key findings include:

• Subchondral bone lesions often precede cartilage degeneration, indicating their central role in OA development and progression.

• Chronic low-grade inflammation of the synovial lining is now recognised as a major contributor to OA, involving both innate and adaptive immune responses.

• Neuroinflammation and central sensitisation are identified as key mechanisms behind chronic OA pain.

• OA is now viewed as a multifactorial joint disease driven by inflammatory and metabolic factors.

• The review emphasises the importance of understanding these mechanisms to inform more effective therapeutic strategies, although detailed treatment approaches are beyond its scope.

Again, I’ve picked out some interesting parts of this review which concern pain processed specifically.

Neuroinflammatory Processes in Osteoarthritis (OA)

• Immune-Nervous System Interactions: Chronic OA pain is influenced by bidirectional communication between the immune and nervous systems at multiple levels:

  • Synovium: Interaction between nociceptors and macrophages.

  • Dorsal Root Ganglion (DRG): Infiltration by macrophages due to peripheral inflammation.

  • Spinal Cord Dorsal Horn: Microglia alter synaptic activity between nociceptors and second-order neurons.

• Central Sensitisation:

  • OA patients show heightened sensitivity to pain even in areas distant from affected joints.

  • This sensitivity is independent of radiological findings, underscoring a neurological basis for OA pain.

• Role of Mast Cells:

  • Mast cells contribute to neuropathic pain and central sensitisation.

  • Nerve damage triggers mast cell degranulation, releasing histamine and nerve growth factor (NGF).

  • These mediators enhance nerve fibre excitability and support persistent pain signalling.

• Mechanism of Sensitisation:

  • Begins with peripheral neuron sensitisation.

  • Leads to excessive neurotransmitter release and hyperexcitability of second-order neurons.

  • Activates microglia, reinforcing the cycle of chronic pain.

Reflections from all three papers

How does this advance your understanding of osteoarthritis? List three key learnings.

Does the information contained here help you to explain to clients the complexity of OA?

Further reading

Yunus MHM, Nordin A, Kamal H. Pathophysiological Perspective of Osteoarthritis. Medicina (Kaunas). 2020 Nov 16;56(11):614. doi: 10.3390/medicina56110614. PMID: 33207632; PMCID: PMC7696673.

References

Coaccioli S, Sarzi-Puttini P, Zis P, Rinonapoli G, Varrassi G. Osteoarthritis: New Insight on Its Pathophysiology. J Clin Med. 2022 Oct 12;11(20):6013. doi: 10.3390/jcm11206013. PMID: 36294334; PMCID: PMC9604603.

Tong, L., Yu, H., Huang, X., Shen, J., Xiao, G., Chen, L., Wang, H., Xing, L., & Chen, D. (2022). Current understanding of osteoarthritis pathogenesis and relevant new approaches. Bone research, 10(1), 60. https://doi.org/10.1038/s41413-022-00226-9