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The Role of Low Intensity Therapeutic Ultrasound in Cartilage Repair and the Underlying Mechanism of Signal Transduction in Human Mesenchymal Stem Cells
Repair and regeneration of cartilage is a biomedical challenge as cartilage lacks self-repair capacity. Factors that impede the success of cartilage repair methods include lack of integration between host cartilage and the graft tissue, inefficient chondrogenesis, hypertrophic differentiation and inflammation that leads to the generation of a biomechanically inferior fibrous tissue, instead of hyaline cartilage. Therefore, therapeutic stimuli that promote cartilage regeneration following clinical procedures is pivotal for the regenerative rehabilitation of cartilage. This study is based on the hypothesis that continuous low-intensity ultrasound (cLIUS) applied at a resonant frequency of 5 MHz promotes native-to-native cartilage integration and maintains hyaline cartilage phenotype ex vivo under non-inflammatory and pro-inflammatory conditions. The hypothesis is predicated on the previous finding that cLIUS-induced bio-effects are maximized at the resonant frequency of 5 MHz. Thus, cLIUS was applied for a period of 28 days to bovine cartilage and osteochondral explants that harbored chondral fissures simulating discontinuity in cartilage. When compared to non-cLIUS-stimulated controls, cLIUS stimulation of explants (a) promoted expeditious closure of chondral fissures in the presence or absence of pro-inflammatory cytokines, IL-6 or TNF?, (b) demonstrated a 3-fold increase in the strength of integration between cartilage interfaces, (c) preserved the distribution of proteoglycans and collagen II. The cLIUS-induced closure of chondral fissures stemmed from the enhanced migration of cells regardless of cytokine insult. Further, cLIUS stimulation abolished the expression of matrix-degrading genes, MMP13 and ADAMTS4, diminished the expression of key pro-inflammatory transcription factor NF-?B, and upregulated cartilage markers, collagen II, TIMP1 and SOX9. The chondrogenic lineage-specific differentiation of mesenchymal stem cells (MSCs) was enhanced under cLIUS, notably in the absence of exogenously added TGF?. cLUS is thus chondro-inductive. The chondrogenic differentiation of MSCs under cLIUS was regulated by the enhanced expression of the transcription factor SOX9, the master regulator of chondrogenesis. The upregulation of SOX9 was related to actin reorganization under cLIUS and was determined to be dependent on the phosphorylation of ERK1/2. In conclusion, the ability of cLIUS in promoting native-to-native cartilage integration coupled with pro-anabolic, anti-catabolic and chondro-inductive response demonstrates the therapeutic potential of cLIUS in improving cartilage repair outcomes.
Sahu, Neety, "The Role of Low Intensity Therapeutic Ultrasound in Cartilage Repair and the Underlying Mechanism of Signal Transduction in Human Mesenchymal Stem Cells" (2019). ETD collection for University of Nebraska-Lincoln. AAI13805348.