Bone innervation and vascularization regulated by osteoclasts contribute to refractive pain-related behavior in the collagen antibody-induced arthritis model
Bibliographic record
Abstract
ABSTRACT Objective Rheumatoid arthritis is often characterized by eroded joints and chronic pain that outlasts disease activity. Whilst several reports show strong associations between bone resorption and nociception, the underlying mechanisms remain to be unraveled. Here, we used the collagen antibody-induced arthritis (CAIA) model to examine the contribution of osteoclasts in pain regulation. The antinociceptive effects of osteoclasts inhibitors and their mechanisms of actions involving bone vascularization and innervation were also explored. Methods BALB/c female mice were subjected to CAIA by intravenous injection of a collagen type-II antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Degree of arthritis, bone resorption, mechanical hypersensitivity, vascularization and innervation in the ankle joint were assessed. Animals were treated with osteoclast inhibitors, zoledronate and cathepsin K inhibitor (T06), and netrin-1 neutralizing antibody. Potential pronociceptive factors were examined in primary osteoclast cultures. Results CAIA induced local bone loss in the calcaneus with ongoing increased osteoclast activity during the inflammatory phase of the model, but not after inflammation has resolved. Mechanical hypersensitivity was reversed by zoledronate in late but not inflammatory phase CAIA. This effect was coupled to the ability of osteoclasts to modulate bone vascularization and innervation, which was inhibited by osteoclast inhibitors. CAIA-induced hypersensitivity in the late phase was also reversed by anti-netrin-1 antibody. Conclusion Osteoclasts induce pain-like behavior in the CAIA model independent of inflammation via effects on bone vascularization and innervation. Key messages What is already known about this subject? Pain and residual signs of erosive lesions are frequently present in rheumatoid arthritis (RA) patients with good disease control Osteoclasts can induce nociceptive signaling but the exact mechanism with respect to RA-induced pain is not clear What does this study add? The pronociceptive actions of osteoclasts extend beyond flares of joint inflammation and erosive activity by increasing bone innervation, bone vascularization and netrin-1 release Osteoclast inhibitors and neutralizing netrin-1 antibodies reverse refractive pain-related behaviors in the collagen antibody-induced arthritis model How might this impact on clinical practice or future developments? This study provides insights to the potential of osteoclast inhibition as a therapeutic strategy for persistent pain in RA
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".