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Inflammation Intensity–Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis
Author(s) -
Li Xiang,
Wang Jianru,
Zhan Zhongping,
Li Sibei,
Zheng Zhaomin,
Wang Taiping,
Zhang Kuibo,
Pan Hehai,
Li Zemin,
Zhang Nu,
Liu Hui
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40468
Subject(s) - wnt signaling pathway , inflammation , wnt3a , ectopic expression , lrp6 , tumor necrosis factor alpha , ankylosing spondylitis , lrp5 , microbiology and biotechnology , beta catenin , signal transduction , medicine , cancer research , chemistry , immunology , biology , cell culture , genetics
Objective To investigate the molecular mechanism underlying inflammation‐related ectopic new bone formation in ankylosing spondylitis ( AS ). Methods Spinal tissues and sera were collected from patients with AS and healthy volunteers and examined for the expression of Wnt proteins. An in vitro cell culture system mimicking the local inflammatory microenvironment of bone‐forming sites was established to study the relationship between inflammation and Wnt expression, the regulatory mechanism of inflammation‐induced Wnt expression, and the role of Wnt signaling in new bone formation. Modified collagen‐induced arthritis ( CIA ) and proteoglycan‐induced spondylitis ( PGIS ) animal models were used to confirm the key findings in vivo. Results The levels of osteoinductive Wnt proteins were increased in sera and spinal ligament tissues from patients with AS . Constitutive low‐intensity tumor necrosis factor ( TNF ) stimulation, but not short‐term or high‐intensity TNF stimulation, induced persistent expression of osteoinductive Wnt proteins and subsequent bone formation through NF ‐κB (p65) and JNK /activator protein 1 (c‐Jun) signaling pathways. Furthermore, inhibition of either the Wnt/β‐catenin or Wnt/protein kinase Cδ ( PKC δ) pathway significantly suppressed new bone formation. The increased expression of Wnt proteins was confirmed in both the modified CIA and PGIS models. A kyphotic and ankylosing phenotype of the spine was seen during long‐term observation in the modified CIA model. Inhibition of either the Wnt/β‐catenin or Wnt/ PKC δ signaling pathway significantly reduced the incidence and severity of this phenotype. Conclusion Inflammation intensity–dependent expression of osteoinductive Wnt proteins is a key link between inflammation and ectopic new bone formation in AS . Activation of both the canonical Wnt/β‐catenin and noncanonical Wnt/ PKC δ pathways is required for inflammation‐induced new bone formation.