BackgroundMuscle atrophy caused by immobilization in the shortened position is characterized by a decrease in the size or cross-sectional area (CSA) of myofibers and decreased muscle length. Few studies have addressed the relationship between limitation of the range of motion (ROM) and the changes in CSA specifically in biarticular muscles after atrophy because of immobilization. We aimed to determine the contribution of 2 distinct muscle groups, the biarticular muscles of the post thigh (PT) and those of the post leg (PL), to the limitation of ROM as well as changes in the myofiber CSAs after joint immobilization surgery.MethodsMale Wistar rats (n = 40) were randomly divided into experimental and control groups. In the experimental group, the left knee was surgically immobilized by external fixation for 1, 2, 4, 8, or 16 weeks (n = 5 each) and sham surgery was performed on the right knee. The rats in the control groups (n = 3 per time point) did not undergo surgery. After the indicated immobilization periods, myotomy of the PT or PL biarticular muscles was performed and the ROM was measured. The hamstrings and gastrocnemius muscles from the animals operated for 1 or 16 weeks were subjected to morphological analysis.ResultsIn immobilized knees, the relative contribution of the PT biarticular myogenic components to the total restriction reached 80% throughout the first 4 weeks and decreased thereafter. The relative contribution of the PL biarticular myogenic components remained <20% throughout the immobilization period. The ratio of the myofiber CSA of the immobilized to that of the sham-operated knees was significantly lower at 16 weeks after surgery than at 1 week after surgery only in the hamstrings.ConclusionsThe relative contribution of the PT and PL components to myogenic contracture did not significantly change during the experimental period. However, the ratio of hamstrings CSAs to the sham side was larger than the ratio of medial gastrocnemius CSAs to the sham side after complete atrophy because of immobilization.

Epithelial-to-mesenchymal transition (EMT) confers cancer cells the ability of invasion and metastasis. However, how does EMT contribute to evasion of immune surveillance is unclear, especially in salivary adenoid cystic carcinoma (SACC). In this study, we investigated the molecular link between EGF-induced EMT and the immune checkpoint ligand programmed death-ligand 1 (PD-L1) by immunoprecipitation (IP) and Westernblot analysis. Cell migration and invasion activity was assayed by transwell assay. Immunohistochemical (IHC) staining analysis was performed for measurement of EMT markers and PD-L1 expression levels in tumor tissues. We found that EGF-induced EGFR activation stabilized Snail expression and induced EMT in SACC. Interestingly, EGFR activation induced simultaneously both EMT and PD-L1 in SACC. Importantly, knockdown of Snail greatly suppressed EGF-induced EMT, but not EGF-induced PD-L1 expression; whereas knockdown of c-Myc strongly repressed PD-L1 expression, but not snail expression and EMT. The molecular link is strongly supported by robust correlations between the EMT markers and PD-L1 expression in human cancer samples.These results suggest that EGFR activated EMT and PD-L1 via two distinct mechanisms. EGFR activation induced EMT and PD-L1 expression in SACC. Snail is required for EGF-induced EMT, but not PD-L1 expression; whereas c-Myc is required for EGFR-mediated PD-L1 upregulation but not EMT. Thus, targeting activated EGFR may inhibit both EMT and PD-L1, which may potentiate the therapeutic effect of PD-L1-based immunotherapy, especially in the malignant subgroups of SACC patients with activated EGFR.

Deteriorated bone quality in osteoporosis challenges the success of implants, which are in urgent need for better early osseointegration as well as antibacterial property for long-term stability. As osteoporotic bone formation tangles with angiogenic clues, the relationship between osteogenesis and angiogenesis has been a novel therapy target for osteoporosis. However, few designs of implant coatings take the compromised osteoporotic angiogenic microenvironment into consideration. Here, we investigated the angiogenic effects of bioactive strontium ions of different doses in HUVECs only and in a co-culture system with BMSCs. A proper dose of strontium ions (0.2–1 mM) could enhance the secretion of VEGFA and Ang-1 in HUVECs as well as in the co-culture system with BMSCs, exhibiting potential to create an angiogenic microenvironment in the early stage that would be beneficial to osteogenesis. Based on the dose screening, we fabricated a bioactive titanium surface doped with zinc and different doses of strontium by plasma electrolytic oxidation (PEO), for the establishment of a microenvironment favoring osseointegration for osteoporosis. The dual bioactive elements augmented titanium surfaces induced robust osteogenic differentiation, and enhanced antimicrobial properties. Augmented titanium implant surfaces exhibited improved bone formation and bone–implant contact under comprehensive assessment of an in vivo bone–implant interface. In conclusion, zinc- and strontium-augmented titanium surface benefits the osseointegration in osteoporosis via promoting osteogenic differentiation, exerting antibacterial efficacy, and stimulating early angiogenesis.

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BackgroundThe differences of mechanical and histological properties between cartilage covered by menisci and uncovered by menisci may contribute to the osteoarthritis after meniscectomy and these differences are not fully understood. The purpose of this study is to investigate potential differences in the mechanical and histological properties, and in particular the collagen architecture, of the superficial cartilage layer and subchondral bone between regions covered and uncovered by menisci using immature knee.MethodsOsteochondral plugs were obtained from porcine tibial cartilage that was either covered or uncovered by menisci. Investigation of the thickness, mechanical properties, histology, and water content of the cartilage as well as micro-computed tomography analysis of the subchondral bone was performed to compare these regions. Collagen architecture was also assessed by using scanning electron microscopy.ResultsCompared to the cartilage uncovered by menisci, that covered by menisci was thinner and showed a higher deformity to compression loading and higher water content. In the superficial layer of cartilage in the uncovered regions, collagen fibers showed high density, whereas they showed low density in covered regions. Furthermore, subchondral bone architecture varied between the 2 regions, and showed low bone density in covered regions.ConclusionsCartilage covered by menisci differed from that uncovered in both its mechanical and histological properties, especially with regards to the density of the superficial collagen layer. These regional differences may be related to local mechanical environment in normal condition and indicate that cartilage covered by menisci is tightly guarded by menisci from extreme mechanical loading. Our results indicate that immature cartilage degeneration and subchondral microfracture may occur easily to extreme direct mechanical loading in covered region after meniscectomy.

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With SAG usage, the hBMSC migration ability was stimulated through CXCR4 elevation while osteogenic differentiation was promoted via the ERK signaling pathway.

The regeneration capacity of osteoporotic bones is generally lower than that of normal bones. Nowadays, alendronate (AL) are orally administrated for osteoporosis due to the inhibition of bone resorption. However, systemic administration of AL is characterized by extremely low bioavailability and high toxicity. In this study, the amino-modified mesoporous bioactive glass scaffolds (N-MBGS) were fabricated by a simple powder processing technique as a novel drug-delivery system for AL. The effects of AL on the osteogenic differentiation of bone mesenchymal stem cells derived from ovariectomized rats (rBMSCs-OVX) were first estimated. The loading efficiency and release kinetics of AL on N-MBGS were investigated in vitro and the osteogenesis of AL-loaded N-MBGS in rat calvarial defect model was detected by micro-CT measurements and the histological assay. Our results revealed that proper concentration of AL significantly promoted osteogenic differentiation of rBMSCs-OVX. The amount and delivery rate of AL were greatly improved through amino modification. Additionally, scaffolds with AL showed better bone formation in vivo, especially for the N-MBGS group. Our results suggest that the novel amino-modified MBGS are promising drug-delivery system for osteoporotic bone defect repairing or regeneration. The experimental schematic of the novel amino-modified MBGS as a promising drug-delivery system for osteoporotic bone regeneration.