Therapeutic blockade of CCL17 in obesity-exacerbated osteoarthritic pain and disease
Kevin Ming-Chin Lee1, Tanya Lupancu1, Stacey N Keenan2
1Faculty of Medicine Dentistry and Health Sciences, Department of Medicine, Royal Melbourne Hospital, Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
Objectives:
We previously reported that CCL17 gene-deficient mice are protected from developing pain-like behaviour and exhibit less disease in destabilization of medial meniscus (DMM)-induced OA, as well as in high-fat diet (HFD)-exacerbated DMM-induced OA. Here, we explored if therapeutic neutralization of CCL17, using increasing doses of a neutralizing monoclonal antibody (mAb), would lead to a dose-dependent benefit in these two models.
Design:
DMM-induced OA was initiated in male mice either fed with a control diet (7% fat) or 8 weeks of a 60% HFD, followed by therapeutic intraperitoneal administration (i.e. when pain is evident) of an anti-CCL17 mAb (B293, 25mg/kg, 5mg/kg or 1mg/kg) or isotype control (BM4; 25mg/kg). Pain-like behaviour and arthritis were assessed by relative static weight distribution and histology, respectively. The effects of B293 (25mg/kg) on HFD-induced metabolic changes, namely oral glucose tolerance test, insulin tolerance test and liver triglyceride levels, were examined.
Results:
Therapeutic administration of B293 results in a dramatic amelioration of DMM-induced OA pain-like behaviour and the inhibition of disease progression, compared to BM4 (isotype control) treatment. A similar therapeutic effect was observed in HFD-exacerbated OA pain-like behaviour and disease. B293 treatment did not alter the measured HFD-induced metabolic changes.
Conclusions:
Based on the data presented, CCL17 could be a therapeutic target in OA patients with joint injury alone or with obesity.
Insights
Therapeutic neutralization of CCL17 significantly reduced pain and disease progression in osteoarthritis models. This suggests CCL17 is a promising therapeutic target for osteoarthritis, even in obese patients.
Area of Science:
- Immunology
- Rheumatology
- Metabolic Diseases
Background:
- CCL17 deficiency protects against osteoarthritis (OA) pain and disease in mouse models.
- CCL17 is implicated in OA pathogenesis, particularly when exacerbated by high-fat diet (HFD).
Purpose of the Study:
- To investigate the therapeutic potential of neutralizing CCL17 using a monoclonal antibody (mAb) in DMM-induced OA and HFD-exacerbated DMM-induced OA mouse models.
- To determine if anti-CCL17 mAb treatment elicits a dose-dependent response.
Main Methods:
- Mice underwent destabilization of the medial meniscus (DMM) surgery with either a control or HFD.
- Therapeutic intraperitoneal administration of anti-CCL17 mAb (B293) at varying doses or an isotype control (BM4) was performed.
- Pain-like behavior and arthritis severity were assessed via weight distribution and histology.
Main Results:
- Anti-CCL17 mAb (B293) treatment significantly ameliorated OA pain-like behavior and inhibited disease progression in both DMM and HFD-exacerbated DMM models.
- The therapeutic benefits were observed compared to isotype control (BM4) treatment.
- B293 treatment did not affect HFD-induced metabolic changes.
Conclusions:
- CCL17 represents a viable therapeutic target for osteoarthritis, applicable to joint injury alone or in conjunction with obesity.
- Neutralizing CCL17 offers a promising therapeutic strategy for managing OA pain and progression.
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