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Targeting GM-CSF for collagenase-induced osteoarthritis pain and disease in mice
K M-C Lee1, V Prasad1, A Achuthan1
1Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia.
Objectives:
Pharmacological options for treating osteoarthritis (OA) are limited and alternative treatments are required. Given the clinical data indicating that granulocyte macrophage-colony stimulating factor (GM-CSF) may be a therapeutic target in human OA, we evaluated different treatment regimens with a neutralizing anti-GM-CSF monoclonal antibody (mAb) in an experimental OA model to determine their effectiveness on amelioration of pain and disease.
Methods:
The collagenase-induced osteoarthritis (CiOA) model was induced in C57BL/6 mice, followed by different treatment regimens of anti-GM-CSF mAb or isotype control. Anti-CCL17 mAb treatment was also administered continually during the late stage of CiOA. Pain-related behavior (change in weight distribution of hind limbs), and disease (cartilage damage and osteophyte size) were assessed.
Results:
Blocking GM-CSF only during early synovitis in CiOA prevented pain and disease development. Once OA pain was established, regardless of the treatment regimen, anti-GM-CSF mAb treatment rapidly and efficiently ameliorated it; however, unless the treatment was continued, pain returned and disease progressed. Continual late stage blockade of GM-CSF was able to ameliorate pain (between-group difference: -6.567; 95% confidence interval (CI): -10.12, -3.011) and suppress cartilage damage (P = 0.0317, 95% CI: -1.75, -0.0556). Continual late stage blockade of CCL17 showed similar effects on pain and disease development.
Conclusions:
Early and short-term GM-CSF neutralization is effective at preventing CiOA pain and disease development but, once pain is evident, continual GM-CSF blockade is required to prevent pain from returning and to suppress disease progression in mice. These data reinforce the potential benefits of anti-GM-CSF (and anti-CCL17) mAb therapy in OA and should inform further clinical trials.
Insights
Early blockade of granulocyte macrophage-colony stimulating factor (GM-CSF) prevents osteoarthritis (OA) pain and disease. Continued treatment is necessary once pain is established to suppress progression, suggesting mAb therapy potential.
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Osteoarthritis (OA) treatment options are limited, necessitating novel therapeutic strategies.
- Granulocyte macrophage-colony stimulating factor (GM-CSF) is implicated as a potential therapeutic target in human OA.
- Monoclonal antibodies (mAbs) offer targeted approaches for immune-mediated diseases.
Purpose of the Study:
- To evaluate the efficacy of different treatment regimens using a neutralizing anti-GM-CSF mAb in an experimental OA model.
- To determine the impact of anti-GM-CSF mAb therapy on pain amelioration and disease progression in OA.
- To explore the therapeutic potential of targeting GM-CSF and CCL17 in OA treatment.
Main Methods:
- Induction of the collagenase-induced osteoarthritis (CiOA) model in C57BL/6 mice.
- Administration of anti-GM-CSF mAb or isotype control across various treatment regimens.
- Assessment of pain-related behaviors and disease markers, including cartilage damage and osteophyte formation.
Main Results:
- Early, short-term blockade of GM-CSF effectively prevented OA pain and disease development.
- Established OA pain was rapidly ameliorated by anti-GM-CSF mAb treatment, but pain returned upon cessation.
- Continuous late-stage GM-CSF blockade significantly reduced pain and cartilage damage, with similar effects observed for anti-CCL17 mAb.
- 95% CI for pain reduction: -10.12 to -3.011; P-value for cartilage damage: 0.0317.
Conclusions:
- Early GM-CSF neutralization can prevent OA development, while continuous blockade is crucial for managing established pain and disease.
- Anti-GM-CSF and anti-CCL17 mAb therapies demonstrate significant potential for OA treatment.
- These findings support the advancement of anti-GM-CSF and anti-CCL17 mAb therapies into clinical trials for OA management.
