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Novel model for the induction of postnatal murine hip deformity.

ABSTRACT: Acetabular dysplasia is a common, multi-etiological, pre-osteoarthritic (OA) feature that can lead to pain and instability of the young adult hip. Despite the clinical significance of acetabular dysplasia, there is a paucity of small animal models to investigate structural and functional changes that mediate morphology of the dysplastic hip and drive the subsequent OA cascade. Utilizing a novel murine model developed in our laboratory, this study investigated the role of surgically induced unilateral instability of the postnatal hip on the initiation and progression of acetabular dysplasia and impingement up to 8-weeks post-injury. C57BL6 mice were used to develop titrated levels of hip instability (i.e., mild, moderate, and severe instabillity or femoral head resection) at weaning. Joint shape, acetabular coverage, histomorphology, and statistical shape modeling were used to assess quality of the hip following 8 weeks of destabilization. Acetabular coverage was reduced following severe, but not moderate, instability. Moderate instability induced lateralization of the femur without dislocation, whereas severe instability led to complete dislocation and pseudoacetabulae formation. Mild instability did not result in morphological changes to the hip. Removal of the femoral head led to reduced hip joint space volume. These data support the notion that hip instability, driven by mechanical loss-of-function of soft connective tissue, can induce morphometric changes in the growing mouse hip. This work developed a new mouse model to study hip health in the murine adolescent hip and is a useful tool for investigating the mechanical and structural adaptations to hip instability during growth. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

SUBMITTER: Killian ML

PROVIDER: S-EPMC6393179 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Novel model for the induction of postnatal murine hip deformity.

Killian Megan L ML Locke Ryan C RC James Michael G MG Atkins Penny R PR Anderson Andrew E AE Clohisy John C JC

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20181119 1

Acetabular dysplasia is a common, multi-etiological, pre-osteoarthritic (OA) feature that can lead to pain and instability of the young adult hip. Despite the clinical significance of acetabular dysplasia, there is a paucity of small animal models to investigate structural and functional changes that mediate morphology of the dysplastic hip and drive the subsequent OA cascade. Utilizing a novel murine model developed in our laboratory, this study investigated the role of surgically induced unila ...[more]

PMID: 30259572

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Project description:BACKGROUND:Due to the post-mitotic nature of myonuclei, postnatal myogenesis is essential for skeletal muscle growth, repair, and regeneration. This process is facilitated by satellite cells through proliferation, differentiation, and subsequent fusion with a pre-existing muscle fiber (i.e., myonuclear accretion). Current knowledge of myogenesis is primarily based on the in vitro formation of syncytia from myoblasts, which represents aspects of developmental myogenesis, but may incompletely portray postnatal myogenesis. Therefore, we aimed to develop an in vitro model that better reflects postnatal myogenesis, to study the cell intrinsic and extrinsic processes and signaling involved in the regulation of postnatal myogenesis. METHODS:Proliferating C2C12 myoblasts were trypsinized and co-cultured for 3 days with 5 days differentiated C2C12 myotubes. Postnatal myonuclear accretion was visually assessed by live cell time-lapse imaging and cell tracing by cell labeling with Vybrant® DiD and DiO. Furthermore, a Cre/LoxP-based cell system was developed to semi-quantitatively assess in vitro postnatal myonuclear accretion by the conditional expression of luciferase upon myoblast-myotube fusion. Luciferase activity was assessed luminometrically and corrected for total protein content. RESULTS:Live cell time-lapse imaging, staining-based cell tracing, and recombination-dependent luciferase activity, showed the occurrence of postnatal myonuclear accretion in vitro. Treatment of co-cultures with the myogenic factor IGF-I (p?<?0.001) and the cytokines IL-13 (p?<?0.05) and IL-4 (p?<?0.001) increased postnatal myonuclear accretion, while the myogenic inhibitors cytochalasin D (p?<?0.001), myostatin (p?<?0.05), and TNF? (p?<?0.001) decreased postnatal myonuclear accretion. Furthermore, postnatal myonuclear accretion was increased upon recovery from electrical pulse stimulation-induced fiber damage (p?<?0.001) and LY29004-induced atrophy (p?<?0.001). Moreover, cell type-specific siRNA-mediated knockdown of myomaker in myoblasts (p?<?0.001), but not in myotubes, decreased postnatal myonuclear accretion. CONCLUSIONS:We developed a physiologically relevant, sensitive, high-throughput cell system for semi-quantitative assessment of in vitro postnatal myonuclear accretion, which can be used to mimic physiological myogenesis triggers, and can distinguish the cell type-specific roles of signals and responses in the regulation of postnatal myogenesis. As such, this method is suitable for both basal and translational research on the regulation of postnatal myogenesis, and will improve our understanding of muscle pathologies that result from impaired satellite cell number or function.

Dataset Information

Novel model for the induction of postnatal murine hip deformity.

Publications

Novel model for the induction of postnatal murine hip deformity.

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