Does aberrantly overexpressed CKIP-1 suppress osteoblast-mediated articular bone repair in inflammatory arthritis?A collagen-induced non-human primate arthritis model

Project: Research project

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Rheumatoid arthritis (RA) is a chronic disease process that is characterized by synovial inflammation and articular bone erosion. In Hong Kong, the prevalence of RA is reported at 0.35%. If not treated, articular bone erosion progresses rapidly and causes joint deformity and functional disability. However, current drugs can only slow or arrest the progression of focal bone erosion, and none to actively promote bone repair. It has been reported that failure repair for bone erosion in RA is caused by inadequate osteoblast-mediated bone formation. Further evidences have demonstrated that the maturation and capability of functional mineralization of osteoblast is compromised at sites of focal bone erosion in inflammatory arthritis. However, the molecular mechanisms still remain largely unknown. Thus, it is necessary to investigate the molecular mechanism responsible for failure of osteoblast-mediated articular bone repair for developing a therapeutic strategy.

Casein kinase-2 interacting protein-1 (CKIP-1) is a negative regulator for bone formation verified by the applicants, which interacts with Smurf1 to enhance its ligase activity to degrade morphogenetic protein (BMP) signaling proteins, e.g. Smad1/5 (Lu K, et al. Nature Cell Biology 2008). In our previous study, we found that aberrant overexpression of CKIP-1 within osteoblasts negatively correlated with bone formation in bone specimens from both patients with RA and rodents with inflammatory arthritis (He X, et al. Bone 2012; He X, et al. Osteoporosis Int 2012). Further, we demonstrated that both the reduction of bone formation and the increase of bone erosion scores were attenuated in osteoblast-specific Ckip-1 knockout mice (Ckip-1osx-/- mice) after induction with type II chicken collagen. Consistently, with the support of previous GRF grants, we found that treatment with osteoblast-targeted delivery of Ckip-1 small interference RNA (Ckip-1 siRNA) promoted bone formation-mediated reparative process at erosive lesion in mice with collagen-induced arthritis (He Xiaojuan, et al. 2015). The above data suggested that CKIP-1 might play an important role in failure of osteoblast-mediated repair for articular bone erosion in RA. Recently, our available data showed that initial increase in CKIP-1 also happened before decrease in bone formation in rhesus monkeys with collagen-induced arthritis, a non-human primate arthritis model shared more similar clinical, histological, genetic, and immunologic features with human RA than rodent arthritis model. Based on the above findings, we further raise our hypothesis that the aberrantly overexpressed CKIP-1 could suppress osteoblast-mediated articular bone repair in a collagen-induced non-human primate arthritis model.

To test the hypothesis towards clinical translation, we have identified a cross-species CKIP-1 siRNA sequence capable of targeting the four species (human, rhesus, rat and mouse), with the high knockdown efficiency in osteoblast-like cells in vitro and rodent bone in vivo (Guo B, et al. Bone 2014). Our established collagen-induced non-human primate arthritis model and targeted delivery system specifically approaching osteoblast lineage cells for RNA interference-based gene silencing (Zhang G, et al. Nature Medicine 2012) will also be introduced to achieve the following five specific aims: (1) To score arthritis severity by a graded scale; (2) To quantify bone architecture by microCT; (3) To score bone destruction by radiographic examination and histologic assessment; (4) To assess local osteoblastic bone formation by bone histomorphometry; (5) To investigate the CKIP-1 expression at mRNA and protein level within osteoblasts by micro-dissection in combination with real-time PCR and western blot, respectively.

This proposal will give further evidence to validate the role of CKIP-1 in failure of osteoblast-mediated repair for articular bone erosion in RA so as to facilitate clinical translation of RNA interference-based therapeutic strategy.
Effective start/end date1/01/1730/06/19

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being


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