Mechanical stress promotes angiogenesis through fibroblast exosomes.

BACKGROUND: Mechanical stress can induce multiple functional changes in vascular endothelial cells, including proliferation, differentiation, and migration. Furthermore, human fibroblasts are susceptible to external mechanical stress. In this work, we investigated whether mechanical stress can induce exosome secretion from fibroblasts to modulate angiogenesis. METHODS: A CCK-8 cell proliferation assay was used to determine mechanical parameters. Then, exosomes from fibroblasts were isolated and characterized with regard to concentration and markers. We subsequently explored the effect of exosomes on proliferation, migration, and angiogenesis. Additionally, high-throughput sequencing was used to screen differentially expressed miRNAs in the mechanical stress-induced exosomes. RESULTS: A static stretching of 15% significantly enhanced the cell viability of the fibroblasts (p < 0.05) and significantly induced the secretion of exosomes from the fibroblasts, which had a stronger internalization ability. Further experiments demonstrated that the presence of static stretching-induced exosomes significantly increased cell proliferation, migration, and angiogenesis by regulating the Erk1/2 signaling pathway. Additionally, 12 up-regulated and 12 down-regulated candidate miRNAs were discriminated in the static stretching-induced exosomes. CONCLUSION: Our findings conclusively demonstrate that static stretching-derived exosomes from fibroblasts promote angiogenesis through differentially expressed miRNAs, providing novel insights into the molecular mechanism by which mechanical stress influences angiogenesis.

Relationship Between Genetic Polymorphisms of the TNF Gene and Hallux Valgus Susceptibility.

Background: Hallux valgus (HV) is a type of forefoot deformity affecting ∼23% of adults. Previous studies have shown that HV is highly heritable. Tumor necrosis factor (TNF) is an important proinflammatory cytokine involved in bone remodeling and plays essential roles in osteoarthritis and chronic inflammatory bone diseases, including HV. Methods: A total of 1,788 Chinese women comprising 637 HV subjects and 1,151 controls were recruited. Twelve single nucleotide polymorphisms (SNPs) located in TNF and its promoter regions were selected and genotyped. Genetic association analyses were performed to investigate potential susceptibility SNPs. Bioinformatic and expression quantitative trait loci (eQTL) analyses were conducted to examine the functional consequences of the SNPs identified as being significantly associated with HV. Results: SNP rs1800629, which is located at the 5' end of the promoter region of TNF, was identified as significantly associated with HV status in Chinese women (OR = 0.56, p = 2.12 × 10-6). Bioinformatic analyses using RegulomeDB indicated that this SNP has important functional significance, but subsequent eQTL analyses did not identify a significant association between rs1800629 and TNF gene expression. In addition, 26 genes with cis-eQTL for rs1800629 were identified. Conclusions: This study identified a susceptibility SNP for HV located within the promoter region of the TNF gene. Bioinformatic and eQTL analyses linked this SNP to 26 genes but not to TNF. Functional studies are needed to more fully characterize the effects of this SNP.

Pathomechanics of hallux valgus: biomechanical and immunohistochemical study.

BACKGROUND: One factor believed to contribute to the development of hallux valgus is an abnormality in collagen structure and makeup of the medial collateral ligament (MCL) of the first metatarsophalangeal joint (MTPJ). We hypothesized that the mechanical properties of the MCL in feet with hallux valgus are significantly different from those in normal feet and that these differences may be related to alterations in the type or distribution of collagen fibers at the interface between the MCL and the bone. MATERIALS AND METHODS: Seven normal fresh-frozen cadaver feet were compared to four cadaver feet that had hallux valgus deformities. The MCL mechanical properties, structure of collagen fibers, and content proportion of type I and type III collagen were determined. RESULTS: The load-deformation and stress-strain curves were curvilinear with three regions: laxity, toe, and linear regions. Laxity of the MCL in feet with hallux valgus was significantly larger than that of normal feet (p = 0.022). Stiffness and tensile modulus in the toe region in feet with hallux valgus were significantly smaller than those in normal feet (p = 0.004); however, stiffness and tensile modulus in the linear region were not significantly different. The MCL collagen fibrils in the feet with hallux valgus had a more wavy distribution than the fibrils in the normal feet. CONCLUSIONS: In general, strong staining for collagen III and to a lesser extent, collagen I was observed at the interface between the MCL and bone in the feet with hallux valgus but not in the normal feet. These results indicate that the abnormal mechanical properties of the MCL in feet with hallux valgus may be related to differences in the organization of collagen I and collagen III fibrils.

Mesenchymal cells and growth factors in bunions.

Bunion formation in adults is an example of bone growth that occurs after physis closure. Bone is laid down secondary to mechanical irritation caused by foot deformity. It is a mechanism of ectopic bone formation unrelated to physeal growth. In this article, bone formation is analyzed using immunohistochemical and cell culture techniques. Using markers specific for mesenchymal cells (collagen type IIa and fibroblast growth factor receptor 3), a cell population is defined in the soft tissues that overlie the bunion and is isolated from explant cultures. The cells do not produce bone matrix in culture, and they do not express osteoblast-related antigens. Stimulation of the cells by fibroblast growth factor (FGF) 2 leads to rapid cell proliferation and phenotype change. The cells start to form humps and at the same time express alkaline phosphatase and collagen type I. Expression of collagen type IIa and fibroblast growth factor receptor 3 ceases. These series of experiments indicate that a specific population of mesenchymal cells occurs in the soft tissues that overlie the bunion. This population is capable of bone formation when stimulated by FGF, a common mediator of inflammatory processes. Thus, FGF stimulation of mesenchymal cells in soft tissues that overlie the head of the first metatarsal is a potential link between the biomechanical forces that cause hallux valgus and bunion formation.

Deposition of amyloid of unknown origin in articular cartilage.

Articular cartilage, obtained from the large toe during hallux valgus operations in 37 patients, was investigated for the presence of amyloid by using the Congo red staining method. Amyloid deposits were demonstrated, particularly in the superficial layer of the cartilage, in 30 cases. This amyloid did not react immunohistochemically with any of the antibodies against the known five major amyloid types (AA, A lambda, A kappa, AF, AB). From these data it is concluded that hyaline cartilage in older individuals is prone to infiltration by an amyloid of a hitherto unidentified class. From the morphological observations there seems to be no correlation between amyloid deposits and the development of osteoarthrosis.