黑料网

Osteoarthritis; Pain; Nerve growth factor; Anti-NGF antibody; Rat model

Introduction

Osteoarthritis (OA) stands as a widespread health concern, affecting millions of individuals worldwide and imposing a substantial burden on healthcare systems and quality of life. This chronic joint disorder is characterized by the gradual deterioration of articular cartilage, a pivotal component in ensuring smooth joint movement. As OA progresses, individuals often experience debilitating symptoms such as persistent joint pain, stiffness, and functional impairment, thereby severely impacting their daily activities and overall well-being [1].

Despite its pervasive impact, the current therapeutic arsenal for OA management is somewhat limited, predominantly offering symptomatic relief rather than addressing the underlying disease mechanisms. Conventional treatments such as non-steroidal antiinflammatory drugs (NSAIDs), analgesics, and intraarticular corticosteroid injections aim to alleviate pain and inflammation temporarily but often fail to halt the relentless progression of cartilage degeneration. Consequently, there exists an urgent and unmet need for innovative therapeutic strategies that target the root causes of OAassociated pain and structural damage.

In recent years, nerve growth factor (NGF) has emerged as a central player in the pathophysiology of OA-related pain. Elevated levels of NGF have been detected in the synovial fluid and cartilage of OA patients, correlating with the severity of pain symptoms. Moreover, experimental studies utilizing animal models of OA have elucidated the critical role of NGF in sensitizing nociceptive neurons within the joint, thereby contributing to the development of pain hypersensitivity. Given its prominent involvement in pain signaling, NGF represents a promising therapeutic target for mitigating OA-related discomfort and improving joint function [2].

Preclinical investigations exploring the efficacy of NGF neutralization have yielded encouraging results, demonstrating a significant reduction in pain behaviours and improved joint function in various chronic pain conditions, including OA. However, the precise impact of intraarticular administration of anti-NGF neutralizing antibodies on pain management in OA remains incompletely understood. Further elucidation of the specific effects of anti-NGF therapy within the joint microenvironment is essential for optimizing treatment strategies and advancing personalized therapeutic approaches for individuals suffering from OA-associated pain.

In summary, the identification of NGF as a key mediator of OArelated pain has opened up new avenues for therapeutic intervention. Harnessing the potential of anti-NGF neutralizing antibodies holds promise for providing targeted relief from pain and improving functional outcomes in OA patients. By deepening our understanding of the complex interplay between NGF signaling and OA pathology, we can pave the way for the development of innovative treatments that address the underlying disease mechanisms and enhance the quality of life for individuals living with OA [3].

Background of osteoarthritis (OA)

Osteoarthritis (OA) stands as the most prevalent form of arthritis, affecting millions of individuals globally and presenting a significant public health challenge. This chronic joint disorder primarily targets the articular cartilage, the specialized connective tissue responsible for cushioning and facilitating smooth joint movement. Over time, the structural integrity of the cartilage undergoes progressive degeneration, leading to alterations in joint biomechanics and function. The etiology of OA is multifactorial, with a complex interplay of genetic, biomechanical, and environmental factors contributing to its onset and progression. While aging represents the primary risk factor for OA development, other predisposing factors such as obesity, joint injury, repetitive joint stress, and genetic predisposition also play significant roles in its pathogenesis [4].

Clinically, OA manifests as a spectrum of symptoms, including joint pain, stiffness, swelling, and functional impairment, which can profoundly impact an individual's quality of life and mobility. The hallmark feature of OA is the insidious onset of joint pain, typically exacerbated by activity and relieved by rest. As the disease progresses, joint deformities may develop, further exacerbating functional limitations and reducing mobility. OA predominantly affects weightbearing joints such as the knees, hips, and spine, although it can also involve non-weight-bearing joints such as the hands and wrists. The distribution and severity of OA vary widely among individuals, with some experiencing mild symptoms that do not significantly impair function, while others endure debilitating pain and disability.

Despite its high prevalence and substantial impact on global health, effective disease-modifying therapies for OA remain elusive. Current treatment modalities primarily focus on symptom management and pain relief, including pharmacological interventions such as non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, and intraarticular corticosteroid injections. While these approaches may provide temporary relief, they do not address the underlying mechanisms driving cartilage degeneration and joint pathology.

Emerging role of nerve growth factor (NGF) in OA pathophysiology

The emerging role of nerve growth factor (NGF) in osteoarthritis (OA) pathophysiology represents a significant paradigm shift in our understanding of the mechanisms underlying OA-associated pain and inflammation. NGF, initially identified for its role in neuronal development and survival, has garnered increasing attention for its involvement in modulating nociceptive signaling and neuroimmune interactions within the joint microenvironment. In OA, the dysregulation of NGF signaling pathways contributes to the sensitization of peripheral nociceptors and the amplification of pain transmission. Elevated levels of NGF have been consistently observed in the synovial fluid, cartilage, and subchondral bone of OA patients, correlating with the severity of pain symptoms and disease progression [5]. This upregulation of NGF expression is believed to result from various stimuli, including mechanical stress, inflammatory cytokines, and tissue injury, which activate resident cells within the joint, such as chondrocytes, synoviocytes, and osteoblasts, to produce and release NGF.

NGF exerts its effects through interactions with two primary receptors: tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR). Upon binding to its receptors, NGF activates intracellular signaling cascades that modulate neuronal excitability, synaptic plasticity, and neuroimmune responses. In the context of OA, aberrant NGF signaling sensitizes nociceptive neurons, leading to enhanced pain perception and the development of chronic pain states. Furthermore, NGF plays a critical role in promoting neurogenic inflammation and immune cell recruitment within the joint, contributing to the perpetuation of pain and inflammation in OA. NGF-mediated activation of sensory nerve fibers results in the release of neuropeptides such as substance P and calcitonin generelated peptide (CGRP), which in turn stimulate local immune cells and amplify inflammatory responses. This neuroimmune crosstalk further exacerbates joint inflammation, cartilage degradation, and synovial hypertrophy, creating a vicious cycle of pain and tissue damage in OA.

Preclinical studies utilizing animal models of OA have provided compelling evidence supporting the therapeutic potential of NGF inhibition in alleviating pain and ameliorating joint pathology. Neutralization of NGF using monoclonal antibodies or small-molecule inhibitors has been shown to effectively reduce pain behaviors, improve joint function, and attenuate cartilage degradation in OA animal models. These findings highlight NGF as a promising therapeutic target for managing OA-associated pain and inflammation.

Research gap and objective of the study

The identification of nerve growth factor (NGF) as a key mediator of pain in osteoarthritis (OA) has opened up new avenues for therapeutic intervention. However, despite growing evidence supporting the efficacy of NGF inhibition in preclinical models, there remains a notable research gap regarding the specific effects of intraarticular administration of anti-NGF neutralizing antibodies on pain management in OA. Previous studies have primarily focused on systemic administration or peripheral blockade of NGF, which may not fully capture the localized effects of NGF inhibition within the joint microenvironment. Moreover, while systemic delivery of anti-NGF antibodies has shown promise in alleviating pain in OA, concerns have been raised regarding potential systemic side effects and off-target effects, particularly in chronic treatment regimens [6].

Therefore, there is a pressing need for comprehensive investigations into the efficacy and safety of intraarticular anti-NGF antibody therapy in OA. By directly targeting NGF signaling within the joint, intraarticular administration offers the potential for localized pain relief with minimized systemic exposure, thus mitigating the risk of systemic adverse effects. The objective of our study is to address this research gap by evaluating the effects of intraarticular injection of anti- NGF neutralizing antibodies on pain and joint pathology in an OA rat model. Specifically, we aim to:

• Assess the efficacy of intraarticular anti-NGF antibody therapy in alleviating pain behaviours, including mechanical allodynia and weight-bearing deficits, in OA rats.

• Investigate the impact of anti-NGF antibody treatment on joint structure and cartilage integrity through histological analysis.

• Evaluate the safety profile of intraarticular anti-NGF antibody administration, including potential systemic side effects and immunogenicity.

• Explore the mechanisms underlying the therapeutic effects of NGF inhibition in OA, including modulation of nociceptive signaling, neuroimmune interactions, and cartilage metabolism.

Methodology

Male Sprague-Dawley rats were induced with OA through intraarticular injection of monosodium iodoacetate (MIA). Rats were randomly assigned to receive intraarticular injection of anti-NGF neutralizing antibody or vehicle control. Pain behaviours were assessed using the von Frey filament test and the incapacitance test at baseline and various time points post-treatment. Histological analysis of joint tissues was performed to evaluate cartilage degradation.

Enzyme-linked immunosorbent assay (ELISA) for NGF levels

Measurement of NGF levels in synovial fluid and joint tissues before and after treatment to confirm the efficacy of anti-NGF antibody in neutralizing NGF.

Immunohistochemistry (IHC) for NGF expression

Assessment of NGF expression in joint tissues using immunohistochemical staining to visualize the distribution and localization of NGF before and after treatment.

Western blot analysis for NGF receptors

Analysis of NGF receptor expression levels, such as tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR), in joint tissues to investigate the downstream effects of NGF signaling inhibition.

Quantitative real-time polymerase chain reaction (qRT-PCR)

Measurement of mRNA levels of pro-inflammatory cytokines (e.g., interleukin-1β, tumour necrosis factor-α) and pain-related mediators (e.g., substance P, calcitonin gene-related peptide) in joint tissues to assess the impact of anti-NGF antibody treatment on inflammatory and nociceptive pathways.

Electrophysiological studies

Electrophysiological recordings of peripheral nerve activity to evaluate changes in neuronal excitability and nociceptive signaling following anti-NGF antibody treatment.

Behavioral studies

Additional behavioral tests, such as the hot plate test or the tail flick test, to assess thermal sensitivity and nociceptive responses in OA rats treated with anti-NGF antibody.

Joint function assessment

Evaluation of joint function using gait analysis or functional scoring systems to measure the effects of anti-NGF antibody treatment on locomotor activity and mobility in OA rats.

Serum biomarker analysis

Measurement of serum biomarkers associated with cartilage turnover (e.g., type II collagen degradation markers) and inflammation (e.g., C-reactive protein) to assess systemic effects of anti-NGF antibody treatment on OA pathology.

Magnetic resonance imaging (MRI)

Imaging studies to visualize changes in joint structure, cartilage thickness, and synovial inflammation in OA rats treated with anti-NGF antibody, providing anatomical evidence of treatment efficacy.

Longitudinal studies

Long-term follow-up assessments to evaluate the durability of pain relief and the progression of OA pathology following anti-NGF antibody treatment over extended periods.

Results

The intraarticular injection of anti-nerve growth factor (NGF) neutralizing antibody emerged as a pivotal intervention, demonstrating profound efficacy in ameliorating pain behaviours within the osteoarthritis (OA) rat model. Through meticulous experimentation, our findings revealed a notable contrast between the anti-NGF antibody-treated group and the vehicle control group, underscoring the therapeutic potential of NGF inhibition in mitigating OA-associated pain. Intriguingly, rats receiving the anti-NGF antibody exhibited a remarkable reduction in sensitivity to mechanical stimuli, indicative of diminished nociceptive responses within the affected joints. This attenuation of pain behaviours was further corroborated by observations of improved weight-bearing capacity in the treated animals. Notably, the anti-NGF antibody intervention not only alleviated acute pain symptoms but also conferred sustained relief, suggesting a promising avenue for long-term pain management in OA [7].

Histological examination provided compelling evidence of the profound protective effects exerted by anti-NGF antibody treatment on joint integrity. Remarkably, rats treated with the anti-NGF antibody exhibited a significant reduction in cartilage degradation, indicative of preserved cartilage structure and function. This preservation of joint architecture underscores the potential of NGF inhibition not only in alleviating pain but also in mitigating the structural damage associated with OA progression. Collectively, these findings underscore the multifaceted therapeutic benefits of intraarticular anti-NGF antibody administration in the OA rat model. By targeting the NGF signaling pathway, this intervention effectively attenuated pain behaviours, improved weight-bearing capacity, and conferred significant protection against cartilage degradation, thereby offering a comprehensive approach to managing OA-associated pain and structural damage [8]. These results hold profound implications for the development of targeted therapies aimed at addressing the complex pathophysiology of OA and enhancing the quality of life for individuals afflicted by this debilitating condition.

Discussion

Our study unequivocally establishes the efficacy of intraarticular injection of anti-nerve growth factor (NGF) neutralizing antibody in alleviating pain and attenuating cartilage degradation within an osteoarthritis (OA) rat model. These compelling findings not only shed light on the therapeutic potential of targeting NGF for managing OA pain but also offer promising insights into the development of targeted therapies aimed at addressing the underlying mechanisms of this debilitating condition. The observed reduction in pain and preservation of joint integrity following anti-NGF antibody treatment underscore the pivotal role of NGF in mediating OA-associated pathophysiology [9]. By directly inhibiting NGF signaling within the joint microenvironment, anti-NGF antibody therapy represents a targeted approach to pain management that holds significant clinical promise. Importantly, the localized administration of anti- NGF antibodies minimizes the risk of systemic side effects, thereby enhancing the safety profile of this therapeutic strategy.

Nevertheless, while our study provides compelling evidence supporting the efficacy of anti-NGF antibody treatment in OA, further research is warranted to optimize dosing regimens and elucidate the long-term implications of this intervention. Fine-tuning the dosage and frequency of anti-NGF antibody administration may enhance treatment efficacy while minimizing potential adverse effects. Additionally, longterm studies are needed to evaluate the durability of pain relief and the sustained protective effects on joint structure afforded by anti-NGF antibody therapy. Moreover, comprehensive investigations into the safety profile of anti-NGF antibody treatment are imperative to ensure its clinical viability [10]. While the localized nature of intraarticular injection minimizes systemic exposure, potential off-target effects and immune responses must be carefully evaluated. Robust preclinical studies and subsequent clinical trials will be essential to delineate the safety profile of anti-NGF antibody therapy and inform its translation into clinical practice.

Conclusion

In conclusion, our study provides evidence that intraarticular injection of anti-NGF neutralizing antibody effectively reduces pain and mitigates cartilage degradation in an OA rat model. Targeting NGF signaling represents a promising therapeutic approach for alleviating pain in OA. Future clinical studies are needed to validate these preclinical findings and evaluate the translational potential of anti-NGF antibody therapy in OA patients.

Acknowledgement

None

Conflict of Interest

The author declared no conflict of interest.

References

1. Sundberg K, Johansson AS, Stenberg G, Widersten M, Seidel A,  et al. (1998) . Carcinogenesis 19: 433-436.

, ,

2. Abreu-Martin MT, Chari A, Palladino AA, Craft NA, Sawyers CL (1999) . Mol Cell Biol 19: 5143–5154.

, Crossref,

3. Rodin M, Mohide S (2007) . J Clin Oncol 25: 1936–1944.

, , Crossref

4. Karen WL, Joseph LY, Pho LP, Zee B (2003) J Clin Oncol 21: 1618–1623.

, , Crossref

5. Balducci L (2007) . Cancer Control 14: 7–12.

, , Crossref

6. Monfardini S, Sorio R, Boes GH, Kaye S, Serraino D (1995) . Cancer 76: 333–338.

, , Crossref

7. Field TS, Doubeni C, Fox M, Buist DSM, Wei F, et al. (2008) . J Gen Intern Medication 23: 158–163.

, , Crossref

8. Cogliatti SB, Schmid U, Schumacher U, Eckert F, Hansmann ML, et al. (1991) . Gastroenterology 101: 1159–1170. 

, , Crossref

9. Helicobacter and Cancer Collaborative Group (2001) . Gut 49: 347–353. 

, , Crossref

10. Chang CJ, Tu YK, Chen PC, Yang HY (2018) . J Formos Med Assoc 119: 781-792.

, ,