ADAMTS9-Regulated Pericellular Matrix Dynamics Governs Focal Adhesion-Dependent Smooth Muscle Differentiation

• Published in: Cell reports (Cambridge) Vol. 23; no. 2; pp. 485 - 498
• Main Authors: Mead, Timothy J., Du, Yaoyao, Nelson, Courtney M., Gueye, Ndeye-Aicha, Drazba, Judith, Dancevic, Carolyn M., Vankemmelbeke, Mireille, Buttle, David J., Apte, Suneel S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2018; Elsevier
• Subjects: Actins - metabolism; ADAMTS9 Protein - antagonists & inhibitors; ADAMTS9 Protein - genetics; ADAMTS9 Protein - metabolism; Animals; Cell Differentiation; Cell Nucleus - metabolism; Cytoskeleton - metabolism; extracellular matrix; Extracellular Matrix - metabolism; Female; focal adhesion; Focal Adhesions - metabolism; Humans; interference reflection microscopy; metalloprotease; Mice; Mice, Transgenic; Microfilament Proteins - metabolism; Muscle Proteins - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; myometrium; Myometrium - metabolism; Myometrium - pathology; parturition; Pregnancy; proteoglycan; proteolysis; RNA Interference; RNA, Small Interfering - metabolism; smooth muscle; uterus; Uterus - cytology; Versicans - metabolism; myometrium; focal adhesion; interference reflection microscopy; uterus; smooth muscle; metalloprotease; extracellular matrix; parturition; proteolysis; proteoglycan
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.034

Focal adhesions anchor cells to extracellular matrix (ECM) and direct assembly of a pre-stressed actin cytoskeleton. They act as a cellular sensor and regulator, linking ECM to the nucleus. Here, we identify proteolytic turnover of the anti-adhesive proteoglycan versican as a requirement for maintenance of smooth muscle cell (SMC) focal adhesions. Using conditional deletion in mice, we show that ADAMTS9, a secreted metalloprotease, is required for myometrial activation during late gestation and for parturition. Through knockdown of ADAMTS9 in uterine SMC, and manipulation of pericellular versican via knockdown or proteolysis, we demonstrate that regulated pericellular matrix dynamics is essential for focal adhesion maintenance. By influencing focal adhesion formation, pericellular versican acts upstream of cytoskeletal assembly and SMC differentiation. Thus, pericellular versican proteolysis by ADAMTS9 balances pro- and anti-adhesive forces to maintain an SMC phenotype, providing a concrete example of the dynamic reciprocity of cells and their ECM. [Display omitted] •ADAMTS9, a secreted metalloproteinase, is required for parturition in mice•ADAMTS9 siRNA impairs focal adhesion formation in uterine smooth muscle cells•ADAMTS9 ensures focal adhesion formation via pericellular versican turnover•Pericellular matrix proteolysis is a crucial regulator of focal adhesions Mead et al. identify a proteolytic mechanism that actively maintains a pericellular microenvironment conducive to uterine smooth muscle activation prior to parturition. They show that pericellular matrix proteolysis by the secreted metalloprotease ADAMTS9 is crucial for maintenance of focal adhesions in uterine smooth muscle cells, and its absence impairs parturition.