The role of osteoblastic CKIP-1 in regulating joint inflammation during rheumatoid arthritis

  • HE, Xiaojuan (PI)

Project: Research project

Project Details


Rheumatoid arthritis (RA) is a chronic autoimmune disease in which activating synovial fibroblasts, macrophages, infiltrating T lymphocytes and leukocytes attack joint structures. However, whether other local cells within joint plays a role in joint inflammation is largely unknown.

Under the support of previous GRF grant (No.261113), we established that CKIP-1 is a negative regulator for bone formation in osteoblasts-mediated bone repair in collagen-induced arthritis (CIA) mice. Surprisingly, we also found that knock-down osteoblastic CKIP-1 attenuated joint inflammation in CIA mice. These results indicated that osteoblastic CKIP-1 promoted joint inflammation in CIA mice. Thereafter, we demonstrated that there was no significantly difference on the severity of joint inflammation between global CKIP-1 knockout (Ckip-1-/-)-CIA mice and osteoblastic CKIP-1 knockout (Ckip-1osx-/-)-CIA mice, which further indicated that CKIP-1’s effect on inflammation was osteoblast specific. Moreover, we also found the attenuated joint inflammation in Ckip-1osx-/--CIA mice were accompanied with decreased IL-1β and IL-6 levels in the joint tissue. Subsequent mechanistic studies revealed that CKIP-1 could promote IL-1β and IL-6 production in TNF-α-induced osteoblast-like cells in cultures, and this action might be via TRAF2-mediated NF-κB signal pathway.

Based on the above observations, we hypothesis that osteoblastic CKIP-1 plays an important role in joint inflammation of RA through TNF-α/TRAF2/NF-κB signal pathway. To test this hypothesis, we will utilize hTNFtg mice. hTNFtg mice spontaneously develop arthritis at the age of four week due to the overexpressed human TNF transgene. We have obtained CKIP-1osx-/-/hTNFtg mice by breeding our CKIP-1osx-/- mice with hTNFtg mice. Using CKIP-1osx-/- mice and CKIP-1osx-/-/hTNFtg mice, we will achieve the following three specific aims: 1. To examine the effect of osteoblastic CKIP-1 on joint inflammation in Ckip-1osx-/-/hTNFtg mice in vivo;
2. To detect the cross-talk between osteoblasts from Ckip-1osx-/- mice and synovial fibroblasts, macrophages, T lymphocytes as well as neutrophils using co-culture system;
3. To determine the mechanism underline the interaction of CKIP-1 with TRAF2.

Our study will uncover the effect of osteoblastic CKIP-1 in regulating joint inflammation and determine how osteoblastic CKIP-1 exerts its effect in inflammation regulation in RA. These hitherto unrecognized functions of osteoblastic CKIP-1 may open a new avenue for the treatment of RA.
Effective start/end date1/01/1930/06/21


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.