Browsing by Subject "Proteoglycan"

Now showing 1 - 3 of 3
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    Functional outcome measures in a surgical model of hip osteoarthritis in dogs.
    (J Exp Orthop, 2016-12) Little, Dianne; Johnson, Stephen; Hash, Jonathan; Olson, Steven A; Estes, Bradley T; Moutos, Franklin T; Lascelles, B Duncan X; Guilak, Farshid
    BACKGROUND: The hip is one of the most common sites of osteoarthritis in the body, second only to the knee in prevalence. However, current animal models of hip osteoarthritis have not been assessed using many of the functional outcome measures used in orthopaedics, a characteristic that could increase their utility in the evaluation of therapeutic interventions. The canine hip shares similarities with the human hip, and functional outcome measures are well documented in veterinary medicine, providing a baseline for pre-clinical evaluation of therapeutic strategies for the treatment of hip osteoarthritis. The purpose of this study was to evaluate a surgical model of hip osteoarthritis in a large laboratory animal model and to evaluate functional and end-point outcome measures. METHODS: Seven dogs were subjected to partial surgical debridement of cartilage from one femoral head. Pre- and postoperative pain and functional scores, gait analysis, radiographs, accelerometry, goniometry and limb circumference were evaluated through a 20-week recovery period, followed by histological evaluation of cartilage and synovium. RESULTS: Animals developed histological and radiographic evidence of osteoarthritis, which was correlated with measurable functional impairment. For example, Mankin scores in operated limbs were positively correlated to radiographic scores but negatively correlated to range of motion, limb circumference and 20-week peak vertical force. CONCLUSIONS: This study demonstrates that multiple relevant functional outcome measures can be used successfully in a large laboratory animal model of hip osteoarthritis. These measures could be used to evaluate relative efficacy of therapeutic interventions relevant to human clinical care.
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    Mechanobiology of the meniscus.
    (J Biomech, 2015-06-01) McNulty, Amy L; Guilak, Farshid
    The meniscus plays a critical biomechanical role in the knee, providing load support, joint stability, and congruity. Importantly, growing evidence indicates that the mechanobiologic response of meniscal cells plays a critical role in the physiologic, pathologic, and repair responses of the meniscus. Here we review experimental and theoretical studies that have begun to directly measure the biomechanical effects of joint loading on the meniscus under physiologic and pathologic conditions, showing that the menisci are exposed to high contact stresses, resulting in a complex and nonuniform stress-strain environment within the tissue. By combining microscale measurements of the mechanical properties of meniscal cells and their pericellular and extracellular matrix regions, theoretical and experimental models indicate that the cells in the meniscus are exposed to a complex and inhomogeneous environment of stress, strain, fluid pressure, fluid flow, and a variety of physicochemical factors. Studies across a range of culture systems from isolated cells to tissues have revealed that the biological response of meniscal cells is directly influenced by physical factors, such as tension, compression, and hydrostatic pressure. In addition, these studies have provided new insights into the mechanotransduction mechanisms by which physical signals are converted into metabolic or pro/anti-inflammatory responses. Taken together, these in vivo and in vitro studies show that mechanical factors play an important role in the health, degeneration, and regeneration of the meniscus. A more thorough understanding of the mechanobiologic responses of the meniscus will hopefully lead to therapeutic approaches to prevent degeneration and enhance repair of the meniscus.
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    Micromechanical Properties of the Extracellular and Pericellular Matrices of Articular Cartilage
    (2013) Wilusz, Rebecca Elizabeth

    The role of articular cartilage in diarthrodial joints is primarily mechanical as the tissue provides a nearly frictionless, load-bearing surface that supports and distributes forces generated during joint loading. Embedded within the extensive cartilage extracellular matrix (ECM), chondrocytes are surrounded by a narrow, distinct pericellular matrix (PCM) that is thought to regulate the biomechanical microenvironment of the cell and influence chondrocyte metabolism, cartilage homeostasis, and overall joint health. While previous studies of PCM mechanical properties required physical extraction of the cell and PCM from the tissue, atomic force microscopy (AFM) provides a means for high resolution microindentation testing that can be used to measure local mechanical properties in situ. This dissertation develops and applies AFM microindentation techniques to 1) evaluate the microscale elastic properties of the cartilage PCM and ECM in situ and 2) correlate site-specific biochemical composition with biomechanical properties of the PCM and ECM.

    An AFM-based stiffness mapping technique was experimentally validated and applied to cartilage sections to evaluate ECM and PCM properties in situ with minimal disruption of native matrix integration. As expected, PCM elastic moduli were significantly less than ECM moduli, uniform with depth, and mechanically isotropic. ECM moduli exhibited distinct depth-dependent anisotropy and unexpectedly, were found to decrease with depth from the articular surface. Both the PCM and ECM exhibited alterations in microscale moduli and their spatial distributions when evaluated in cartilage presenting early degenerative changes associated with osteoarthritis (OA) as compared to healthy tissue.

    The ability to correlate site-specific biochemical composition with local biomechanical properties provides a more complete characterization of the chondrocyte microenvironment. To this end, we developed novel immunofluorescence (IF)-guided AFM stiffness mapping and demonstrated that PCM mechanical properties correlate with the presence of type VI collagen. Extending this technique by using dual IF, we presented new evidence for a defining role of perlecan in the PCM, showing that interior regions of the PCM rich in perlecan and type VI collagen exhibit lower elastic moduli than peripheral PCM and ECM regions lacking perlecan. Furthermore, lower moduli at the PCM interior were significantly influenced by the presence of heparan sulfate. IF-guided AFM stiffness mapping was combined with enzymatic digestion to demonstrate that the micromechanical properties of the PCM exhibit high resistance to specific enzymatic digestion of aggrecan and aggrecan-associated glycosaminoglycans but are vulnerable to proteolytic degradation by leukocyte elastase.

    Overall, this research generates new insights into the complex structural, compositional, and functional relationships between the cartilage ECM and PCM and provides the tools and framework for further studies to continue to investigate their importance in regulating chondrocyte physiology in health and disease.