Traditionally, understanding differentiation pathway has been achieved by studying biochemical signal pathways controlled by various growth factors and cytokines. However, since various physical factors including tissue stiffness and topology can also determine the differentiation pathway of stem cells, mechanobiological pathway for controlling differentiation has been emphasized. Moreover, newly identified mechanobiological pathways have encouraged efforts to interpret stem cell differentiation in terms of cell-material interaction and provided clues to accurately design microenvironment of stem cells to control the direction of differentiation. Cells continuously recognize topographical and mechanical properties of the surrounding microenvironment and modulate their functional phenotypes through appropriate physiological responses to maintain homeostasis. Cell-cell and cell-extracellular matrix (ECM) interactions determine physical connections between the outside and the inside of individual cells to regulate various cellular functions, including adhesion, migration, proliferation, and cell differentiation. [3] Integrin, a transmembrane protein, is actively involved in outside-in and inside-out signaling mediated by polymerization and contraction of the cytoskeleton known to control cellular mechanotransduction pathways. [4] Therefore, a changed physical microenvironment can be detected by integrin-ECM interaction which has been traditionally considered as a primary target for controlling cell behavior through the material properties. Recent studies have shown that nuclear mechanosensation is a key process in response to physical stimuli. Nuclear membrane is tightly connected to integrin-based focal adhesion through cytoskeletal fibers that can transmit external force or cytoskeletal tension to the nuclear membrane, causing structural deformation of the nucleus. [5] Applied force not only changes nuclear shape, but also determines the conformation of many proteins located in nuclear membrane associated with various biochemical signals. [6] Since transcriptional regulatory mechanisms, such as histone modification and transcription factor activity, are controlled by force-mediated nuclear deformation, signal pathways for nuclear mechanosensation have been focused to interpret cellular adaptation mechanism including stem cell differentiation. [7] Various methods have been used to determine cell functions by changing cell adhesion through the corresponding changes in external substrates using micropatterned cell confinement, micro-/nanosized topographic substrates, and substrate stiffness. Micropatterning of ECM proteins is a well-established method to Recent findings about cell fate change induced by physical stimuli have expedited the discovery of underlying regulatory mechanisms that determine stem cell differentiation. Progress with regards to micro-/nanofabrication technology have led to the development of advanced materials that can mimic biophysical features of in vivo related circumstances of the human body...
The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4 + T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.
In this study, we demonstrated a significant induction of LCN2 expression in astrocytes of the optic nerve following EAON induction. Our results imply that astrocyte-derived LCN2 may have a pivotal role in the development of demyelinating optic neuritis, and LCN2 can be a therapeutic target to alleviate immune and inflammatory damage in the optic nerve.
Objective. Interleukin-10 (IL-10) is a pleiotropic immunoregulatory cytokine with a chondroprotective effect that is elevated in cartilage and synovium in patients with osteoarthritis. However, the role of IL-10 during endochondral bone formation and its mechanism of action have not been elucidated.Methods. IL-10 -/-mice and IL-10-treated tibial organ cultures were used to study loss and gain of IL-10 functions, respectively, during endochondral bone formation. Primary chondrocytes from the long bones of mouse embryos were cultured with and without IL-10. To assess the role of IL-10 in chondrogenic differentiation, we conducted mesenchymal cell micromass cultures.Results The main pathologic feature of osteoarthritis (OA) is gradual loss of cartilage from exposure to repetitive loading. The initial response of chondrocytes to external mechanical loading is adaptation; that is, they become metabolically active and proliferative (1). However, repetitive stress induces hypertrophic differentiation and, eventually, chondrocyte apoptosis. During this process, the balance between anabolic and catabolic signaling pathways in which SOX9 and RUNX-2, respectively, function as major regulatory transcription factors is critical in determining the fate of chondrocytes (2,3). Several cytokines can affect the expression of SOX9 and RUNX-2 via complex autocrine and paracrine loops and, as a consequence, have an effect on the progression of OA (4,5).The physiologic and pathologic roles of the main catabolic cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor ␣ (TNF␣), have been well established in chondrocyte biology (4).
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