Inflammation Intensity-Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis

被引：74

作者：

Li, Xiang ^{[1
]}

Wang, Jianru ^{[1
,2
]}

Zhan, Zhongping ^{[1
]}

Li, Sibei ^{[3
]}

Zheng, Zhaomin ^{[1
,2
]}

Wang, Taiping ^{[4
]}

Zhang, Kuibo ^{[5
]}

Pan, Hehai ^{[1
]}

Li, Zemin ^{[1
]}

Zhang, Nu ^{[1
]}

Li, Hui ^{[1
,2
]}

机构：

[1] Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China

[2] Guangdong Prov Key Lab Orthopaed & Traumatol, Guangzhou, Guangdong, Peoples R China

[3] Guangzhou Chest Hosp, Guangzhou, Guangdong, Peoples R China

[4] Second Peoples Hosp, Chengdu, Sichuan, Peoples R China

[5] Sun Yat Sen Univ, Affiliated Hosp 5, Zhuhai, Peoples R China

来源：

ARTHRITIS & RHEUMATOLOGY | 2018年 / 70卷 / 07期

基金：

中国国家自然科学基金;

关键词：

TUMOR-NECROSIS-FACTOR; MESENCHYMAL STEM-CELLS; RADIOGRAPHIC PROGRESSION; MOUSE MODEL; TNF-ALPHA; OSTEOGENIC DIFFERENTIATION; INDUCED ARTHRITIS; ACTIVATION; AGGRECAN; SPONDYLOARTHRITIS;

D O I：

10.1002/art.40468

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective: To investigate the molecular mechanism underlying inflammation-related ectopic new bone formation in ankylosing spondylitis (AS). MethodsSpinal 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-B (p65) and JNK/activator protein 1 (c-Jun) signaling pathways. Furthermore, inhibition of either the Wnt/-catenin or Wnt/protein kinase C (PKC) 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/-catenin or Wnt/PKC 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/-catenin and noncanonical Wnt/PKC pathways is required for inflammation-induced new bone formation.

引用

页码：1056 / 1070

页数：15

共 26 条

[1] INFLAMMATION INTENSITY-DEPENDENT EXPRESSION OF OSTEOINDUCTIVE WNT PROTEINS IS CRITICAL FOR ECTOPIC NEW BONE FORMATION IN ANKYLOSING SPONDYLITIS
Liu, H.
Li, X.
Wang, J.
ANNALS OF THE RHEUMATIC DISEASES, 2018, 77 : 618 - 619
[2] The Long, Dynamic Journey to the Elucidation of the Links Between Inflammation, Ectopic Bone Formation, and Wnt Signaling in Ankylosing Spondylitis
Kwon, Seong-Ryul
JOURNAL OF RHEUMATIC DISEASES, 2022, 29 (01): : 1 - 3
[3] Introduction: Inflammation and new bone formation in ankylosing spondylitis
Sieper, J.
CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, 2008, 26 (04) : 717 - 717
[4] Purine metabolites promote ectopic new bone formation in ankylosing spondylitis
Zhang, Shuqiong
Fan, Zhidan
Ouyang, Zijun
Sun, Haiyan
Song, Yue
Yu, Haiguo
Xu, Qiang
Liu, Shijia
Sun, Yang
Shao, Fenli
INTERNATIONAL IMMUNOPHARMACOLOGY, 2023, 116
[5] Relationship between inflammation and new bone formation in patients with Ankylosing spondylitis
Baraliakos, Xenofon
Listing, J.
Rudwaleit, M.
Sieper, J.
Braun, Juergen
ARTHRITIS AND RHEUMATISM, 2008, 58 (09): : S945 - S946
[6] The relationship between inflammation and new bone formation in patients with ankylosing spondylitis
Xenofon Baraliakos
Joachim Listing
Martin Rudwaleit
Joachim Sieper
Juergen Braun
Arthritis Research & Therapy, 10
[7] Evidence for a link between inflammation and new bone formation in ankylosing spondylitis
Baraliakos, X.
Listing, J.
Rudwaleit, M.
Brandt, J.
Sieper, J.
Braun, J.
ANNALS OF THE RHEUMATIC DISEASES, 2008, 67 : A39 - A40
[8] The relationship between inflammation and new bone formation in patients with ankylosing spondylitis
Baraliakos, X.
Listing, J.
Rudwaleit, M.
Brandt, J.
Sieper, J.
Braun, J.
CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, 2008, 26 (04) : 733 - 733
[9] The relationship between inflammation and new bone formation in patients with ankylosing spondylitis
Baraliakos, Xenofon
Listing, Joachim
Rudwaleit, Martin
Sieper, Joachim
Braun, Juergen
ARTHRITIS RESEARCH & THERAPY, 2008, 10 (05)
[10] Resolution of Inflammation Following Treatment of Ankylosing Spondylitis Is Associated with New Bone Formation
Pedersen, Susanne J.
Chiowchanwisawakit, Praveena
Lambert, Robert G. W.
Ostergaard, Mikkel
Maksymowych, Walter P.
JOURNAL OF RHEUMATOLOGY, 2011, 38 (07) : 1349 - 1354

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