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An in vitro cell culture system mimicking the local inflammatory microenvironment of bone\u2010forming sites was established to study the relationship between inflammation and Wnt expression, the regulatory mechanism of inflammation\u2010induced Wnt expression, and the role of Wnt signaling in new bone formation. Modified collagen\u2010induced arthritis (\n                      <jats:styled-content style=\"fixed-case\">CIA<\/jats:styled-content>\n                      ) and proteoglycan\u2010induced spondylitis (\n                      <jats:styled-content style=\"fixed-case\">PGIS<\/jats:styled-content>\n                      ) animal models were used to confirm the key findings in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The levels of osteoinductive Wnt proteins were increased in sera and spinal ligament tissues from patients with\n                      <jats:styled-content style=\"fixed-case\">AS<\/jats:styled-content>\n                      . Constitutive low\u2010intensity tumor necrosis factor (\n                      <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\n                      ) stimulation, but not short\u2010term or high\u2010intensity\n                      <jats:styled-content style=\"fixed-case\">TNF<\/jats:styled-content>\n                      stimulation, induced persistent expression of osteoinductive Wnt proteins and subsequent bone formation through\n                      <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\n                      \u2010\u03baB (p65) and\n                      <jats:styled-content style=\"fixed-case\">JNK<\/jats:styled-content>\n                      \/activator protein 1 (c\u2010Jun) signaling pathways. Furthermore, inhibition of either the Wnt\/\u03b2\u2010catenin or Wnt\/protein kinase C\u03b4 (\n                      <jats:styled-content style=\"fixed-case\">PKC<\/jats:styled-content>\n                      \u03b4) pathway significantly suppressed new bone formation. The increased expression of Wnt proteins was confirmed in both the modified\n                      <jats:styled-content style=\"fixed-case\">CIA<\/jats:styled-content>\n                      and\n                      <jats:styled-content style=\"fixed-case\">PGIS<\/jats:styled-content>\n                      models. A kyphotic and ankylosing phenotype of the spine was seen during long\u2010term observation in the modified\n                      <jats:styled-content style=\"fixed-case\">CIA<\/jats:styled-content>\n                      model. Inhibition of either the Wnt\/\u03b2\u2010catenin or Wnt\/\n                      <jats:styled-content style=\"fixed-case\">PKC<\/jats:styled-content>\n                      \u03b4 signaling pathway significantly reduced the incidence and severity of this phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Inflammation intensity\u2013dependent expression of osteoinductive Wnt proteins is a key link between inflammation and ectopic new bone formation in\n                      <jats:styled-content style=\"fixed-case\">AS<\/jats:styled-content>\n                      . Activation of both the canonical Wnt\/\u03b2\u2010catenin and noncanonical Wnt\/\n                      <jats:styled-content style=\"fixed-case\">PKC<\/jats:styled-content>\n                      \u03b4 pathways is required for inflammation\u2010induced new bone formation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.40468","type":"journal-article","created":{"date-parts":[[2018,2,26]],"date-time":"2018-02-26T15:22:41Z","timestamp":1519658561000},"page":"1056-1070","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Inflammation Intensity\u2013Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis"],"prefix":"10.1002","volume":"70","author":[{"given":"Xiang","family":"Li","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital, Sun Yat\u2010sen University Guangzhou 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