Xiang Li1, Jianru Wang2, Zhongping Zhan1, Sibei Li3, Zhaomin Zheng2, Taiping Wang4, Kuibo Zhang5, Hehai Pan1, Zemin Li1, Nu Zhang1, Hui Liu2. 1. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 2. The First Affiliated Hospital, Sun Yat-sen University and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China. 3. Guangzhou Chest Hospital, Guangzhou, China. 4. The Second People's Hospital, Chengdu, China. 5. The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.
Abstract
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 (PKCδ) 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/PKCδ 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/PKCδ pathways is required for inflammation-induced new bone formation.
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 (PKCδ) 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/PKCδ 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/PKCδ pathways is required for inflammation-induced new bone formation.
Authors: Di Yan; Johann E Gudjonsson; Stephanie Le; Emanual Maverakis; Olesya Plazyo; Christopher Ritchlin; Jose U Scher; Roopesh Singh; Nicole L Ward; Stacie Bell; Wilson Liao Journal: J Invest Dermatol Date: 2021-07-22 Impact factor: 8.551