A Friction Testing-Bioreactor Device for Study of Synovial Joint Biomechanics, Mechanobiology, and Physical Regulation.

In primary osteoarthritis (OA), normal 'wear and tear' associated with aging inhibits the ability of cartilage to sustain its load-bearing and lubrication functions, fostering a deleterious physical environment. The frictional interactions of articular cartilage and synovium may influence joint homeostasis through tissue level wear and cellular mechanotransduction. To study these mechanical and mechanobiological processes, a device capable of replicating the motion of the joint is described. The friction testing device controls the delivery of reciprocal translating motion and normal load to two contacting biological counterfaces. This study adopts a synovium-on-cartilage configuration, and friction coefficient measurements are presented for tests performed in a phosphate-buffered saline (PBS) or synovial fluid (SF) bath. The testing was performed for a range of contact stresses, highlighting the lubricating properties of SF under high loads. This friction testing device can be used as a biomimetic bioreactor for studying the physical regulation of living joint tissues in response to applied physiologic loading associated with diarthrodial joint articulation.

Attachment of cartilage wear particles to the synovium negatively impacts friction properties.

Cartilage wear particles are released into the synovial fluid by mechanical and chemical degradation of the articular surfaces during osteoarthritis and attach to the synovial membrane. Accumulation of wear particles could alter key tissue-level mechanical properties of the synovium, hindering its characteristically low-friction interactions with underlying articular surfaces in the synovial joint. The present study employs a custom loading device to further the characterization of native synovium friction properties, while investigating the hypothesis that attachment of cartilage wear particles increases friction coefficient. Juvenile bovine synovium demonstrated characteristically low friction coefficients in sliding contact with glass, in agreement with historical measurements. Friction coefficient increased with higher normal load in saline, while lubrication with native synovial fluid maintained low friction coefficients at higher loads. Cartilage wear particles generated from juvenile bovine cartilage attached directly to synovium explants in static culture, with incorporation onto the tissue denoted by cell migration onto the particle surface. In dilute synovial fluid mimicking the decreased lubricating properties during osteoarthritis, wear particle attachment significantly increased friction coefficient against glass, and native cartilage and synovium. In addition to providing a novel characterization of synovial joint tribology this work highlights a potential mechanism for cartilage wear particles to perpetuate the degradative environment of osteoarthritis by modulating tissue-level properties of the synovium that could impact macroscopic wear as well as mechanical stimuli transmitted to resident cells.

Emerging insights into the comparative effectiveness of anabolic therapies for osteoporosis.

Over the past three decades, the mainstay of treatment for osteoporosis has been antiresorptive agents (such as bisphosphonates), which have been effective with continued administration in lowering fracture risk. However, the clinical landscape has changed as adherence to these medications has declined due to perceived adverse effects. As a result, decreases in hip fracture rates that followed the introduction of bisphosphonates have now levelled off, which is coincident with a decline in the use of the antiresorptive agents. In the past two decades, two types of anabolic agents (including three new drugs), which represent a novel approach to improving bone quality by increasing bone formation, have been approved. These therapies are expected to lead to a new clinical paradigm in which anabolic agents will be used either alone or in combination with antiresorptive agents to build new bone and reduce fracture risk. This Review examines the mechanisms of action for these anabolic agents by detailing their receptor-activating properties for key cell types in the bone and marrow niches. Using these advances in bone biology as context, the comparative effectiveness of these anabolic agents is discussed in relation to other therapeutic options for osteoporosis to better guide their clinical application in the future.

Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo.

Irisin, a skeletal-muscle secreted myokine, facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In this study, we investigated whether irisin directly regulates osteoclasts. In vitro, irisin (2-10 ng/mL) increased osteoclast differentiation in C57BL/6J mouse bone marrow progenitors; however, this increase was blocked by a neutralizing antibody to integrin αVß5. Irisin also increased bone resorption on several substrates in situ. RNAseq revealed differential gene expression induced by irisin including upregulation of markers for osteoclast differentiation and resorption, as well as osteoblast-stimulating 'clastokines'. Forced expression of the irisin precursor Fndc5 in transgenic C57BL/6J mice resulted in lower bone mass at three ages and greater in vitro osteoclastogenesis from Fndc5-transgenic bone marrow progenitors. This study demonstrates that irisin acts directly on osteoclast progenitors to increase differentiation and promote bone resorption, supporting the tenet that irisin not only stimulates bone remodeling but may also be an important counter-regulatory hormone.

Cartilage Wear Particles Induce an Inflammatory Response Similar to Cytokines in Human Fibroblast-Like Synoviocytes.

The synovium plays a key role in the development of osteoarthritis, as evidenced by pathological changes to the tissue observed in both early and late stages of the disease. One such change is the attachment of cartilage wear particles to the synovial intima. While this phenomenon has been well observed clinically, little is known of the biological effects that such particles have on resident cells in the synovium. The present work investigates the hypothesis that cartilage wear particles elicit a pro-inflammatory response in diseased and healthy human fibroblast-like synoviocytes, like that induced by key cytokines in osteoarthritis. Fibroblast-like synoviocytes from 15 osteoarthritic human donors and a subset of three non-osteoarthritic donors were exposed to cartilage wear particles, interleukin-1α or tumor necrosis factor-α for 6 days and analyzed for proliferation, matrix production, and release of pro-inflammatory mediators and degradative enzymes. Wear particles significantly increased proliferation and release of nitric oxide, interleukin-6 and -8, and matrix metalloproteinase-9, -10, and -13 in osteoarthritic synoviocytes, mirroring the effects of both cytokines, with similar trends in non-osteoarthritic cells. These results suggest that cartilage wear particles are a relevant physical factor in the osteoarthritic environment, perpetuating the pro-inflammatory and pro-degradative cascade by modulating synoviocyte behavior at early and late stages of the disease. Future work points to therapeutic strategies for slowing disease progression that target cell-particle interactions. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1979-1987, 2019.

A Functional Tissue-Engineered Synovium Model to Study Osteoarthritis Progression and Treatment.

IMPACT STATEMENT: The synovium envelops the diarthrodial joint and plays a key regulatory role in defining the composition of the synovial fluid through filtration and biosynthesis of critical boundary lubricants. Synovium changes often precede cartilage damage in osteoarthritis. We describe a novel in vitro tissue engineered model, validated against native synovium explants, to investigate the structure-function of synovium through quantitative solute transport measures. Synovium was evaluated in the presence of a proinflammatory cytokine, interleukin-1, or the clinically relevant corticosteroid, dexamethasone. We anticipate that a better understanding of synovium transport would support efforts to develop more effective strategies aimed at restoring joint health.

Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1α.

Fibroblast-like synoviocytes (FLS) reside in the synovial membrane of diarthrodial joints and are exposed to a dynamic fluid environment that presents both physical and chemical stimuli. The ability of FLS to sense and respond to these stimuli plays a key role in their normal function, and is implicated in the alterations to function that occur in osteoarthritis (OA). The present work characterizes the response of FLS to fluid flow-induced shear stress via real-time calcium imaging, and tests the hypothesis that this response is modulated by interleukin-1α (IL-1α), a cytokine elevated in OA. FLS demonstrated a robust calcium signaling response to fluid shear that was dose dependent upon stress level and required both external and internal calcium sources. Preconditioning with 10ng/mL IL-1α for 24h heightened this shear stress response by significantly increasing the percent of responding cells and peak magnitude, while significantly decreasing the time for a peak to occur. Intercellular communication via gap junctions was found to account for a portion of the FLS population response in normal conditions, and was significantly increased by IL-1α preconditioning. IL-1α was also found to significantly increase average length and incidence of the primary cilium, an organelle commonly implicated in shear mechanosensing. These findings suggest that the elevated levels of IL-1α found in the OA environment heighten FLS sensitivity to fluid shear by altering both intercellular communication and individual cell sensitivity, which could affect downstream functions and contribute to progression of the disease state.