Omoto Takenori, Yimiti Dilimulati, Sanada Yohei, Toriyama Minoru, Ding Chenyang, Hayashi Yuta, Ikuta Yasunari, Nakasa Tomoyuki, Ishikawa Masakazu, Sano Masayuki, Lee Minjung, Akimoto Takayuki, Shukunami Chisa, Miyaki Shigeru, Adachi Nobuo
Department of Orthopaedic Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
Front Cell Dev Biol. 2022 Jun 14;10:898428. doi: 10.3389/fcell.2022.898428. eCollection 2022.
Tendon is a fibrous connective tissue, that is, transmitting the forces that permit body movement. However, tendon/ligament biology is still not fully understood and especially, the role of miRNAs in tendon/ligament is sparse and uncharacterized in models. The objectives of this study were to address the function of DICER using mice with tendon/ligament-specific deletion of ( conditional knockout; cKO), and to identify key miRNAs in tendon/ligament. cKO mice exhibited hypoplastic tendons through structurally abnormal collagen fibrils with downregulation of tendon-related genes. The fragility of tendon did not significantly affect the tensile strength of tendon in cKO mice, but they showed larger dorsiflexion angle in gait compared with Control mice. We identified two miRNAs, miR-135a and miR-1247, which were highly expressed in the Achilles tendon of Control mice and were downregulated in the Achilles tendon of cKO mice compared with Control mice. miR-135a mimic increased the expression of tendon-related genes in injured Achilles tendon-derived fibroblasts. In this study, cKO mice exhibited immature tendons in which collagen fibrils have small diameter with the downregulation of tendon-related genes such as transcriptional factor, extracellular matrix, and miRNAs. Thus, DICER plays an important role in tendon maturation, and miR-135a may have the potential to become key miRNA for tendon maturation and healing.
肌腱是一种纤维结缔组织，即传递允许身体运动的力量。然而，肌腱/韧带生物学仍未被完全理解，尤其是微小RNA（miRNA）在肌腱/韧带中的作用在模型中还很稀少且未被表征。本研究的目的是利用肌腱/韧带特异性缺失DICER的小鼠（条件性敲除；cKO）来探讨DICER的功能，并确定肌腱/韧带中的关键miRNA。cKO小鼠的肌腱发育不全，胶原纤维结构异常，且肌腱相关基因表达下调。肌腱的脆弱性并未显著影响cKO小鼠肌腱的拉伸强度，但与对照小鼠相比，它们在步态中表现出更大的背屈角度。我们鉴定出两种miRNA，即miR-135a和miR-1247，它们在对照小鼠的跟腱中高表达，与对照小鼠相比，在cKO小鼠的跟腱中表达下调。miR-135a模拟物增加了损伤的跟腱来源的成纤维细胞中肌腱相关基因的表达。在本研究中，cKO小鼠表现出不成熟的肌腱，其中胶原纤维直径较小，且肌腱相关基因如转录因子、细胞外基质和miRNA表达下调。因此，DICER在肌腱成熟中起重要作用，miR-135a可能有潜力成为肌腱成熟和愈合的关键miRNA。
