Fibulin-4 is required for the mechanical stability of tendons

Sasaki T, Jin K, Takimoto A, Taga Y, Ishikawa Y, Bächinger HP, Sakai T, Terabayashi T, Hanada K, Schlötzer-Schrehardt U, Shukunami C, Hiraki Y, Nakamura T, Yamamoto E (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Cell and Tissue Research Springer

DOI: 10.1007/s00441-025-04028-3

Abstract

Fibulin-4, an extracellular matrix protein, is indispensable for elastic fiber assembly. Fibulin-4 null mice show bilateral forelimb contracture and patients with EFEMP2/FBLN4 mutations demonstrate similar defects, besides joint laxity, vascular and pulmonary abnormalities. Here we report that limb tendons in fibulin-4 null mice developed normally until E17.5–18.5, but thereafter　thinner tendons showed abnormalities, suggesting that fibulin-4 maintains the integrity of certain tendons. Tendon/ligament specific conditional knockout mice of Efemp2/Fbln4 (ScxCre-H;Fbln4flox/− mice) were generated in order to elucidate its role of collagen fibril organization, collagen cross-linking and mechanical features of tendons. Curiously, however, the conditional Fbln4 knockout mice did not show forelimb contractures or other obvious morphological defects. We could detect small amounts of fibulin-4 in tendon extracts, but isolated tenocytes from the conditional knockout mice did not secrete fibulin-4, confirming that the Efemp2/Fbln4 gene was properly deleted in tenocytes. Electron microscopic analyses revealed an enhanced proportion of thinner fibrils in tendons from the conditional knockout mice. Furthermore, mechanical stress tests of patellar tendons of the conditional knockout mice revealed strongly reduced strain resistance compared to the tendons of control mice, although cross-link formation and thermal stability of tendon collagen were not affected. These finding indicate that fibulin-4 has an important role in the organization and stability of collagen fibrils in tendons.

Authors with CRIS profile

Ursula Schlötzer-Schrehardt Department of Ophthalmology

Involved external institutions

Oita University / 大分大学 JP Japan (JP) Kyoto University / 京都大学 Kyōto daigaku JP Japan (JP) Nippi, Incorporated / 株式会社ニッピ JP Japan (JP) Fujita Health University JP Japan (JP) Kansai Medical University JP Japan (JP) Kindai University / 近畿大学 JP Japan (JP)

How to cite

APA:

Sasaki, T., Jin, K., Takimoto, A., Taga, Y., Ishikawa, Y., Bächinger, H.P.,... Yamamoto, E. (2025). Fibulin-4 is required for the mechanical stability of tendons. Cell and Tissue Research. https://doi.org/10.1007/s00441-025-04028-3

MLA:

Sasaki, Takako, et al. "Fibulin-4 is required for the mechanical stability of tendons." Cell and Tissue Research (2025).

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