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Does aberrantly overexpressed casein kinase-2 interacting protein-1
contribute to failure of osteoblast-mediated repair for bone erosion
in rheumatoid arthritis?
Rheumatoid arthritis (RA) is a severe, aggressive and debilitating disease, characterized by
pain, swelling and progressive destruction of synovial joints. Consequently, patients with severe
disease face significant disability, deformity, and irreversible joint damage. Bone erosion is the
main reason leading to joint dysfunction, which is due to excessive osteoclast-mediated bone
resorption and inadequate osteoblast-mediated bone formation. However, osteoblast-mediated
repair of bone erosion in RA seems limited or occurs only infrequently during current combination
It has been reported that mid- to late-stage differentiation of osteoblast toward maturation and
capability of functional mineralization is compromised at sites of focal bone erosion in inflammatory
arthritis. However, the molecular mechanism remains largely unknown. Thus, it is necessary to
investigate the molecular mechanism responsible for osteoblast function to identify a target for
developing a novel therapeutic strategy.
Recently, the applicants have reported a newly discovered intracellular negative regulator
casein kinase-2 interacting protein-1 (CKIP-1) for controlling osteoblast lineage cells from mid- to
late-stage differentiation toward functional mineralization, which interacts Smurf1 and enhances its
ligase activity for promoting proteasomal degradation of anabolic bone morphogenetic protein
(BMP) signaling proteins, e.g. Smad1 (Lu K, et al. Nature Cell Biology 2008; Zhang G, et al.
Nature Medicine 2012
). Further, the applicants found that CKIP-1 protein level was sharply higher
whereas Smad1 protein and osteocalcin mRNA levels were significantly lower in eroded bone
specimen from RA patients when compared to that from age-matched non-RA subjects (Songlin
). Consistently, our recently available data suggested the increased CKIP-1 expression
within osteoblast well correlated with both reduced bone formation and progressive bone erosion in
rodents with adjuvant-induced arthritis or collagen-induced arthritis (Xiaojuan He 2012A, 2012B
Thereafter, the applicants demonstrated that proinflammatory cytokines involved in RA (TNF-,
IL-1 and IL-6) could up-regulate CKIP-1 protein expression in dose-dependent manner in
osteoblast-like cells in vitro
(Chao Liang 2012A
). Moreover, the above data not only advanced our
previous findings that CKIP-1 could be involved in cytokine signaling response, but also provided
potential explanation for the reduced BMP signaling activity and subsequent decrease in bone
formation within RA-like lesion in TNF transgenic mice. Taken together, the applicants have the
following hypothesis that aberrantly overexpressed CKIP-1 could play an important role in failure of
osteoblast-mediated repair for articular bone erosion in RA.
To test the hypothesis, the applicants have generated osteoblast-specific CKIP-1
) based on the Cre-loxP strategy (Chao Liang 2012B
osteoblast-targeted delivery of CKIP-1 small interference RNA ((DSS)6-liposome-CKIP-1 siRNA)
(Zhang G 2012)
. Our established induction protocol (Liu DY 2012; Xiao C 2011; Li J 2011
collagen-induced arthritis and K/BxN serum-transfer arthritis will be introduced in adult CKIP-1
and control littermate males, respectively, to achieve the following four specific aims: (1) To detect
mice after induction with type II bovine collagen for inflammatory
arthritis; (2) To detect bone phenotypes in CKIP-1
mice after induction with K/BxN serum for
inflammatory arthritis; (3) To evaluate rescues in articular bone erosion by (DSS)6-liposome-CKIP-1
siRNA in inflammatory arthritic mice induced by type II bovine collagen; (4) To evaluate rescues in
articular bone erosion by (DSS)6-liposome-CKIP-1 siRNA in inflammatory arthritic mice induced by
The current proposal would help provide a potential target CKIP-1 and a novel therapeutic
strategy to augment osteoblast- mediated bone formation toward repairing articular bone erosion in
CONTENTS Development of organic farming in Wallonia , PhD. Scientific Attache Philippe BURNY – Walloon Center for Agricultural Research, Professor Gembloux Agro-Bio Tech, University of Liege Gembloux (Belgium), Scientific Attache Frederic DEBODE – Wallon Center for Agricultural Research, Gembloux (Belgium): Biodiversity and ecosystem approach as political discourse , PhD. Assis
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