Inhibition of Integrin αvβ6 Activation of TGF-β Attenuates Tendinopathy

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2022 Feb 15

PMID 35166070

Authors

Xiao Wang

Shen Liu

Tao Yu

Senbo An

Ruoxian Deng

Xiaohua Tan

Janet Crane

Weixin Zhang

Dayu Pan

Mei Wan

Andrew Carr

Xu Cao

Affiliations

Soon will be listed here.

Abstract

Tendinopathy is a common tendon disorder that causes pain and impairs function. It is the most common reason for consultation with musculoskeletal specialists. The available therapies for tendinopathy are limited in number and efficacy and have unclear cellular and molecular mechanisms. Here it is shown that transforming growth factor-beta (TGF-β) activated by integrin αvβ6 promotes tendinopathy in mice. Excessive active TGF-β is found during tendinopathy progression, which led to tenocytes' phenotype transition to chondrocytes. Transgenic expression of active TGF-β in tendons induced spontaneous tendinopathy, whereas systemic injection of a TGF-β neutralizing antibody attenuated tendinopathy. Inducible knockout of the TGF-β type 2 receptor gene (Tgfbr2) in tenocytes inhibited tendinopathy progression in mice. Moreover, it is found that integrin αvβ6 induces TGF-β activation in response to mechanical load in tendons. Conditional knockout of the integrin αv gene in tendons prevented tendinopathy in mice. The study suggests that integrin αvβ6 activation of TGF-β is the mechanism of tendinopathy, and that integrin αvβ6 may be a therapeutic target in tendinopathy.

Citing Articles

CTHRC1 Attenuates Tendinopathy via Enhancing EGFR/MAPK Signaling Pathway.

Chen C, Zheng X, Wang C, Zhou H, Zhang Y, Ye T Adv Sci (Weinh). 2024; 11(47):e2406611.

PMID: 39540237 PMC: 11653680. DOI: 10.1002/advs.202406611.

Myeloid Cells and Sensory Nerves Mediate Peritendinous Adhesion Formation via Prostaglandin E2.

Zhang X, Xiao Y, Tao Z, Zhang Y, Cheng X, Liu X Adv Sci (Weinh). 2024; 11(40):e2405367.

PMID: 39207041 PMC: 11516151. DOI: 10.1002/advs.202405367.

Cross-Talk between the TGF-β and Cell Adhesion Signaling Pathways in Cancer.

Liao J, Chen R, Lin B, Deng R, Liang Y, Zeng J Int J Med Sci. 2024; 21(7):1307-1320.

PMID: 38818471 PMC: 11134594. DOI: 10.7150/ijms.96274.

Whole Genome Expression Profiling of Semitendinosus Tendons from Children with Diplegic and Tetraplegic Cerebral Palsy.

Nemska S, Serio S, Larcher V, Beltrame G, Portinaro N, Bang M Biomedicines. 2023; 11(11).

PMID: 38001919 PMC: 10669597. DOI: 10.3390/biomedicines11112918.

The Contribution of the Nrf2/ARE System to Mechanotransduction in Musculoskeletal and Periodontal Tissues.

Fragoulis A, Tohidnezhad M, Kubo Y, Wruck C, Craveiro R, Bock A Int J Mol Sci. 2023; 24(9).

PMID: 37175428 PMC: 10177782. DOI: 10.3390/ijms24097722.

References

Perlman R, Schiemann W, Brooks M, Lodish H, Weinberg R . TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol. 2001; 3(8):708-14. DOI: 10.1038/35087019. View

Forde M, Punnett L, Wegman D . Prevalence of musculoskeletal disorders in union ironworkers. J Occup Environ Hyg. 2005; 2(4):203-12. DOI: 10.1080/15459620590929635. View

Sengkerij P, Vos R, Weir A, van Weelde B, Tol J . Interobserver reliability of neovascularization score using power Doppler ultrasonography in midportion achilles tendinopathy. Am J Sports Med. 2009; 37(8):1627-31. DOI: 10.1177/0363546509332255. View

Hynes R . The extracellular matrix: not just pretty fibrils. Science. 2009; 326(5957):1216-9. PMC: 3536535. DOI: 10.1126/science.1176009. View

Maeda T, Sakabe T, Sunaga A, Sakai K, Rivera A, Keene D . Conversion of mechanical force into TGF-β-mediated biochemical signals. Curr Biol. 2011; 21(11):933-41. PMC: 3118584. DOI: 10.1016/j.cub.2011.04.007. View

Magne D, Bougault C . What understanding tendon cell differentiation can teach us about pathological tendon ossification. Histol Histopathol. 2015; 30(8):901-10. DOI: 10.14670/HH-11-614. View

Shukunami C, Takimoto A, Oro M, Hiraki Y . Scleraxis positively regulates the expression of tenomodulin, a differentiation marker of tenocytes. Dev Biol. 2006; 298(1):234-47. DOI: 10.1016/j.ydbio.2006.06.036. View

Pryce B, Watson S, Murchison N, Staverosky J, Dunker N, Schweitzer R . Recruitment and maintenance of tendon progenitors by TGFbeta signaling are essential for tendon formation. Development. 2009; 136(8):1351-61. PMC: 2687466. DOI: 10.1242/dev.027342. View

Archambault J, Jelinsky S, Lake S, Hill A, Glaser D, Soslowsky L . Rat supraspinatus tendon expresses cartilage markers with overuse. J Orthop Res. 2007; 25(5):617-24. DOI: 10.1002/jor.20347. View

10.

Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T . Latent TGF-β structure and activation. Nature. 2011; 474(7351):343-9. PMC: 4717672. DOI: 10.1038/nature10152. View

11.

Wang X, Liu S, Yu T, An S, Deng R, Tan X . Inhibition of Integrin αvβ6 Activation of TGF-β Attenuates Tendinopathy. Adv Sci (Weinh). 2022; 9(11):e2104469. PMC: 9009110. DOI: 10.1002/advs.202104469. View

12.

Jarvinen T . Neovascularisation in tendinopathy: from eradication to stabilisation?. Br J Sports Med. 2019; 54(1):1-2. PMC: 6923943. DOI: 10.1136/bjsports-2019-100608. View

13.

James R, Kesturu G, Balian G, Chhabra A . Tendon: biology, biomechanics, repair, growth factors, and evolving treatment options. J Hand Surg Am. 2008; 33(1):102-12. DOI: 10.1016/j.jhsa.2007.09.007. View

14.

Yelin E, Weinstein S, King T . The burden of musculoskeletal diseases in the United States. Semin Arthritis Rheum. 2016; 46(3):259-260. DOI: 10.1016/j.semarthrit.2016.07.013. View

15.

Solomon L, Russell B, Watson L, Beier F, Berube N . Targeted loss of the ATR-X syndrome protein in the limb mesenchyme of mice causes brachydactyly. Hum Mol Genet. 2013; 22(24):5015-25. DOI: 10.1093/hmg/ddt351. View

16.

Heinemeier K, Olesen J, Haddad F, Langberg H, Kjaer M, Baldwin K . Expression of collagen and related growth factors in rat tendon and skeletal muscle in response to specific contraction types. J Physiol. 2007; 582(Pt 3):1303-16. PMC: 2075262. DOI: 10.1113/jphysiol.2007.127639. View

17.

van der Flier A, Sonnenberg A . Function and interactions of integrins. Cell Tissue Res. 2001; 305(3):285-98. DOI: 10.1007/s004410100417. View

18.

Riley G . Tendinopathy--from basic science to treatment. Nat Clin Pract Rheumatol. 2008; 4(2):82-9. DOI: 10.1038/ncprheum0700. View

19.

Wang X, Li F, Xie L, Crane J, Zhen G, Mishina Y . Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice. Nat Commun. 2018; 9(1):551. PMC: 5803194. DOI: 10.1038/s41467-018-02988-5. View

20.

Robinson J, Cook J, Purdam C, Visentini P, Ross J, Maffulli N . The VISA-A questionnaire: a valid and reliable index of the clinical severity of Achilles tendinopathy. Br J Sports Med. 2001; 35(5):335-41. PMC: 1724384. DOI: 10.1136/bjsm.35.5.335. View