Tenascin-C, a novel target to inhibit new bone formation in axial spondyloarthritis, linked with inflammation, mechanical strain and tissue damage

Mechelen, Margot Van; Lories, Rik

doi:10.1136/annrheumdis-2021-220443

Cited by 4 publications

(5 citation statements)

References 19 publications

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“…However, despite all recent advances in training of physicians and in imaging, a diagnostic delay remains a concern for patients with AS ( 9 ). For those patients in whom disease activity has been already too high for too long or in whom the process of bone remodeling already has started and solely stopping inflammation will not suffice anymore, no targeted treatment to retard the progression of disease at the level of bone structure is currently available ( 10 ). Late-stage patients with severe spinal kyphosis often required high-risk corrective surgery with various complication.…”

Section: Introductionmentioning

confidence: 99%

CXCL12/CXCR4-Rac1–mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis

Cui

Chen

et al. 2022

Sci. Adv.

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Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by inflammatory back pain and spinal ankylosis due to pathological new bone formation. Here, we identified CXCL12 as a critical contributor to pathological new bone formation through recruitment of osteogenic precursor cells (OPCs). CXCL12 was found highly expressed in the regions that would potentially develop pathological new bone. OPCs were recruited to the regions where CXCL12 was up-regulated. Inhibition of CXCL12/CXCR4 axis with AMD3100 or conditional knockout of CXCR4 attenuated OPCs migration and subsequent pathological new bone formation in animal models of AS. By contrast, a genetically engineered animal model with CXCL12 overexpression developed a joint ankylosis phenotype. Furthermore, Rac1 was found essential for OPCs migration and pathological new bone formation. These findings ravel the novel role of CXCL12 in AS and indicate a potential strategy for targeting the CXCL12/CXCR4-Rac1 axis to prevent progression of axial skeleton ankylosis.

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Section: Introductionmentioning

confidence: 99%

CXCL12/CXCR4-Rac1–mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis

Cui

Chen

et al. 2022

Sci. Adv.

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“…Also, as a part of its mechanism, TN-C may bind to several cell surface receptors, such as heparan sulfate proteoglycans and integrins, to modify cytoskeletal organization and cell spreading in arthritic joint diseases [23]. Since TN-C is a key driver of new bone formation and our study's findings showed increased levels in non-TNFi patients, targeting TN-C may provide an alternative strategy for patients with high disease activity due to delayed diagnosis or whose bone remodeling process has already begun, making it no longer adequate to just stop the inflammation [24].…”

Section: Discussionmentioning

confidence: 75%

Tenascin-C and Interleukin-17 Up-regulation in Axial Spondyloarthritis Patients

Al-Hindawi¹,

Al-Gebori²,

Alosami³

2023

RBJ

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Background: Axial spondyloarthritis (axSpA) is an inflammatory, systemic rheumatic condition that mostly affects the axial skeleton. Tenascin-C (TN-C) is a hexameric glycoprotein of considerable size, upregulated in many inflammatory conditions, while Interleukin-17 (IL-17) a cytokine that plays an important role in SpA symptoms. Objective: to investigate the upregulation between the serum levels of TN-C and IL-17 in Iraqi axSpA patients and the disease characteristics. Patients and Methods: Seventy-four axSpA patients and 28 matched controls were studied. Fifty-four patients received a tumor necrosis factor inhibitor (TNFi) and 20 did not. Serum TN-C and IL-17 concentrations were determined using the ELISA technique. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was assessed. For statistical tests, Chi Square, Mann Whitney, Independent Samples T, and Pearson's correlation tests are used. Results: Patients mean age was 35.6±0.9 years, 65 males and 9 females, and disease duration was 5.18±0.6 years. 47.4% were smokers, 47% had inflammatory low back pain, and HLA-B27 was present in 91%. BASDAI mean was 6.1±0.4 in non-TNFi and 2.6±0.3 in those on TNFi. The serum TN-C concentration was significantly increased in patients, especially those on non-TNFi (79±9.6 pg/mL) compared to those on TNFi (69.1±3.2 pg/mL) and control (53±3.9 pg/mL) (p=0.003). Serum IL-17 was significantly elevated in those receiving TNFi (877.9±257 pg/mL) compared to non-TNFi (487.2±234 pg/mL) and control (182.4±36.6 pg/mL) (p=0.033). The TN-C significantly correlated with erythrocyte sedimentation rate (r=0.27, p=0.02) and with hemoglobin (Hb) concentration (r=0.26, p=0.02). TN-C and IL-17 were non-significantly related (r=0.14, p=0.2). Conclusions: axSpA Patients demonstrated high levels of serum TN-C, particularly in those not receiving TNFi, and high IL-17 levels in those receiving TNFi, suggesting that there is an association with tissue injury from the disease and stimulation of immunological and resident tissue cells. Patients who had not received TNFi showed significantly higher disease activity than others.

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“…Furthermore, in a latest milestone study, a secreted extracellular matrix protein, tenascin‐C (TNC), is proven to be aberrantly induced by TNF‐α, IL‐17A and IL‐22 in ligament and entheseal tissues in AS patients. The inhibition of TNC could significantly suppress new bone formation both in vitro and in vivo 28,29 . Interestingly, TNC also actively participates in atherosclerotic plaque/aneurysm formation, 30 which suggests that TNC might be a key molecule to align aorta‐vertebrae remodeling.…”

Section: Discussionmentioning

confidence: 99%

“…The inhibition of TNC could significantly suppress new bone formation both in vitro and in vivo. 28,29 TNC also actively participates in atherosclerotic plaque/aneurysm formation, 30 which suggests that TNC might be a key molecule to align aorta-vertebrae remodeling.…”

Section: Discussionmentioning

confidence: 99%

Inflammation, new bone formation and aorta

Chen

Zhou

et al. 2022

Int J of Rheum Dis

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The formation of osteophytes in general is attributed to aging, mechanical stress and local inflammation; however, the precise pathophysiology remains to be clarified. [1][2][3] In ankylosing spondylitis (AS), osteophytes develop in the enthesis at the annulus bone junction of the vertebral body and eventually bridge the adjacent vertebrae, namely syndesmophytes, which are the hallmarks of the disease. 1,[3][4][5] A well-conceived intriguing observation is that osteophytes or syndesmophytes tend to spare the aorta side, as characterized in a non-inflammatory disease, diffuse idiopathic skeletal hyperostosis (DISH), with prominent continuous right-sided syndesmophytes away from aorta (left-sided). 6 In a recent report using a semiautomated method based on computed tomography (CT) scans, Tan et al illustrated that in AS, syndesmophytes are also less frequent and smaller in the area of the vertebral rim adjacent to the aorta than in neighboring regions in the lower thoracic and upper lumbar

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Tenascin-C, a novel target to inhibit new bone formation in axial spondyloarthritis, linked with inflammation, mechanical strain and tissue damage

Abstract: Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Patient consent for publication Not required.Provenance and peer review Commissioned; externally peer reviewed.

Cited by 4 publications

References 19 publications

CXCL12/CXCR4-Rac1–mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis

CXCL12/CXCR4-Rac1–mediated migration of osteogenic precursor cells contributes to pathological new bone formation in ankylosing spondylitis

Tenascin-C and Interleukin-17 Up-regulation in Axial Spondyloarthritis Patients

Inflammation, new bone formation and aorta

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