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The Monoiodoacetate Model of Osteoarthritis Pain in the Mouse
Published on: May 16, 2016
Acute systemic macrophage depletion in osteoarthritic mice alleviates pain-related behaviors and does not affect
Terese Geraghty1,2, Shingo Ishihara1,2, Alia M Obeidat1,2
1Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, Chicago, IL, USA.
Background:
Osteoarthritis (OA) is a painful degenerative joint disease and a leading source of years lived with disability globally due to inadequate treatment options. Neuroimmune interactions reportedly contribute to OA pain pathogenesis. Notably, in rodents, macrophages in the DRG are associated with onset of persistent OA pain. Our objective was to determine the effects of acute systemic macrophage depletion on pain-related behaviors and joint damage using surgical mouse models in both sexes.
Methods:
We depleted CSF1R + macrophages by treating male macrophage Fas-induced apoptosis (MaFIA) transgenic mice 8- or 16-weeks post destabilization of the medial meniscus (DMM) with AP20187 or vehicle control (10 mg/kg i.p., 1x/day for 5 days), or treating female MaFIA mice 12 weeks post partial meniscectomy (PMX) with AP20187 or vehicle control. We measured pain-related behaviors 1-3 days before and after depletion, and, 3-4 days after the last injection we examined joint histopathology and performed flow cytometry of the dorsal root ganglia (DRGs). In a separate cohort of male 8-week DMM mice or age-matched naïve vehicle controls, we conducted DRG bulk RNA-sequencing analyses after the 5-day vehicle or AP20187 treatment.
Results:
Eight- and 16-weeks post DMM in male mice, AP20187-induced macrophage depletion resulted in attenuated mechanical allodynia and knee hyperalgesia. Female mice showed alleviation of mechanical allodynia, knee hyperalgesia, and weight bearing deficits after macrophage depletion at 12 weeks post PMX. Macrophage depletion did not affect the degree of cartilage degeneration, osteophyte width, or synovitis in either sex. Flow cytometry of the DRG revealed that macrophages and neutrophils were reduced after AP20187 treatment. In addition, in the DRG, only MHCII + M1-like macrophages were significantly decreased, while CD163 + MHCII- M2-like macrophages were not affected in both sexes. DRG bulk RNA-seq revealed that Cxcl10 and Il1b were upregulated with DMM surgery compared to naïve mice, and downregulated in DMM after acute macrophage depletion.
Conclusions:
Acute systemic macrophage depletion reduced the levels of pro-inflammatory macrophages in the DRG and alleviated pain-related behaviors in established surgically induced OA in mice of both sexes, without affecting joint damage. Overall, these studies provide insight into immune cell regulation in the DRG during OA.
Insights
Depleting macrophages in the dorsal root ganglia (DRG) reduced osteoarthritis pain in mice without worsening joint damage. This study highlights the role of immune cells in chronic OA pain management.
Area of Science:
- Immunology
- Neuroscience
- Orthopedics
Background:
- Osteoarthritis (OA) is a major cause of disability globally, with limited treatment options.
- Neuroimmune interactions, particularly involving macrophages in the dorsal root ganglia (DRG), are implicated in OA pain.
- Understanding these interactions is crucial for developing effective OA pain therapies.
Purpose of the Study:
- To investigate the impact of acute systemic macrophage depletion on pain behaviors and joint pathology in mouse models of osteoarthritis.
- To determine the specific effects of macrophage depletion on immune cell populations within the DRG.
Main Methods:
- Surgically induced osteoarthritis models (destabilization of the medial meniscus and partial meniscectomy) were used in male and female mice.
- Systemic depletion of CSF1R+ macrophages was achieved using AP20187 in MaFIA transgenic mice.
- Pain behaviors, joint histopathology, DRG flow cytometry, and DRG bulk RNA-sequencing were performed.
Main Results:
- Macrophage depletion significantly alleviated pain-related behaviors (mechanical allodynia, hyperalgesia, weight-bearing deficits) in both sexes with established OA.
- Joint damage (cartilage degeneration, osteophytes, synovitis) was not affected by macrophage depletion.
- DRG analysis revealed reduced macrophages and neutrophils, specifically a decrease in pro-inflammatory MHCII+ M1-like macrophages, following treatment.
Conclusions:
- Acute systemic macrophage depletion effectively reduces OA pain in mice by targeting pro-inflammatory macrophages in the DRG.
- This approach alleviates pain without exacerbating joint structural damage.
- These findings offer valuable insights into the role of DRG immune cell regulation in OA pathogenesis and pain.
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