Qi Liu,1,2,* Nan Nan,1,2,* Wenfang Li,1,2 Mengwei Dong,1,2 Wei Pu,1,2 Yang Liu,1,2 Jie Zhao,3 Huiqin Hao1,2 

1Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Chinese Medicine, Jinzhong, 030619, People’s Republic of China; 2Engineering Research Center of Cross Innovation for Chinese Traditional Medicine of Shanxi Province, Jinzhong, 03619, People’s Republic of China; 3Shanxi Provincial Key Laboratory of Classical Prescription Strengthening Yang, Taiyuan, 030013, People’s Republic of China

*These authors contributed equally to this work

Correspondence:Huiqin Hao, Email hhq@sxtcm.edu.cn

Background: Rheumatoid arthritis (RA) is a synovial inflammation-associated autoimmune disease with secondary osteoporosis. Pain is the most important symptom of RA, and some patients with well-controlled inflammation may still experience pain.
Purpose: To explore the relationship and dynamic changes between synovial inflammation and pain and bone destruction in collagen-induced arthritis (CIA) model rats, and to choose a better time window for drug treatment.
Methods: The CIA model rats were constructed for 1, 2, 3, and 4-week groups. The changes were observed by joint swelling and behavioral assessment. The paw mechanical withdrawal threshold (PWT) was used for pain assessment. The micro-CT was used to assess joint injury and bone destruction. The biomechanics were performed to evaluate tension and compression test. The histological staining was used to observe ankle joint pathology. The immunohistochemical staining and Western blot were used to estimate the expression of calcitonin gene-related peptide (CGRP) and c-fos.
Results: The results showed that the degree of joint swelling, synovial hyperplasia, and inflammatory response were alleviated to varying extents over time. However, there were no significant changes in bone destruction, osteoclasts, or the maximum load of compression and tension. It showed secondary osteoporosis from the first week of the CIA model with no significant changes during the course of the experiment. There was no significant improvement in the PWT, and the expression of CGRP and c-fos was significantly increased over time, indicating hyperalgesia aggravation. Additionally, the result showed that repeated open-field tests might reduce the total distance of spontaneous movement.
Conclusion: The results suggested that the pain and joint inflammation might not be synchronized, possibly related to post-inflammatory hyperalgesia. CIA model could be used for the study of pain, also relatively stable and suitable for the study of RA with secondary osteoporosis.

Keywords: collagen-induced arthritis rats, temporal changes, inflammation, pain, secondary osteoporosis