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Sonic hedgehog (SHH) is abundantly expressed and critical for morphogenesis in embryonic lungs, however, SHH expression drops to a much lower level in mice from E17.5 and in humans from the 21st gestational week. We find that SHH expression is robustly up-regulated in the airway epithelia of children with asthma or mouse models with allergic airway disease. Specifically, airway-specific SMO loss of function significantly suppresses allergen-induced goblet cell phenotypes, whereas an airway-specific SMO gain of function markedly enhances the goblet cell phenotypes in mouse models with allergic airway disease. Notably, intratracheal administration with SHH- neutralizing antibody or cyclopamine robustly attenuates goblet cell phenotypes in mouse models with allergic airway disease. Finally, we identify that Muc5AC gene encoding MUC5AC mucin serves as a direct target of GLI transcriptional factors in response to SHH, whereas the SAM pointed domain-containing ETS transcription factor and Forkhead box A2, critical transcriptional factors for goblet cell phenotypes, both function as the effectors of GLIs in response to SHH stimulation. Together, the up-regulation of SHH expression in allergic bronchial epithelia contributes to goblet cell metaplasia; thus, blockage of SHH signaling is a rational approach in a therapeutic intervention of epithelial remodeling in chronic airway diseases.

Cdc42, a member of Rho family small guanosine triphosphatases (GTPases), is critical for cartilage development. We investigated the roles of Cdc42 in osteoarthritis and explored the potential mechanism underlying Cdc42-mediated articular cartilage degeneration and subchondral bone deterioration. Cdc42 is highly expressed in both articular cartilage and subchondral bone in a mouse osteoarthritis model with surgical destabilization of the medial meniscus (DMM) in the knee joints. Specifically, genetic disruption of Cdc42, knockdown of Cdc42 expression, or inhibition of Cdc42 activity robustly attenuates the DMM-induced destruction, hypertrophy, high expression of matrix metallopeptidase-13 and collagen X, and activation of Stat3 in articular cartilages. Notably, genetic disruption of Cdc42, knockdown of Cdc42 expression or inhibition of Cdc42 activity significantly restored the increased numbers of mesenchymal stem cells, osteoprogenitors, osteoblasts, osteoclasts, and neovascularized vessels, the increased bone mass, and the activated Erk1/2, Smad1/5 and Smad2 in subchondral bone of DMM-operated mice. Mechanistically, Cdc42 mediates interleukin-1β-induced interleukin-6 production and subsequent Jak/Stat3 activation to regulate chondrocytic inflammation, and also lies upstream of Erk/Smads to regulate subchondral bone remodeling during transform growth factor-β1 signaling. Cdc42 is apparently required for both articular cartilage degeneration and subchondral bone deterioration of osteoarthritis, thus, interventions targeting Cdc42 have potential in osteoarthritic therapy. © 2018 American Society for Bone and Mineral Research.

No abstract

Background: Three-dimensional (3D) printing involves the layering of seed cells, biologically compatible scaffolds, and biological activity factors to precisely recapitulate a biological tissue. Graphene oxide (GO), a type of micro material, has been utilized as a small molecule-transport vehicle. With the proliferation of GO, the biocompatibility of chondrocytes in a microenvironment constructed by 3D printed scaffolds and GO is innovative. Accordingly, we speculate that, as a type of micro material, GO can be used with 3D scaffolds for a uniform distribution in the cartilage layer. Results: A qualitative analysis of the chondrocyte-proliferation potential revealed that the culture of 3D printing with a 10% GO scaffold was higher than that of the other groups. Meanwhile, the progress of cell apoptosis was activated. Through scanning electron microscopy, immunofluorescence, and in vivo research, we observed that the newborn cartilage matrix extended along the border of the cartilage and scaffold and matured. After an analysis with immunohistochemical staining with aggrecan and collagen I, the cartilage following the 3D-printed scaffold was thinner than that of the 3D-printed GO scaffold. Furthermore, the collagen I of the cartilage expression in treatment with the GO scaffold was significant from week 2 to 6. Conclusions: The findings indicate that a 3D-printed GO scaffold can potentially be utilized for the construction of a cartilage matrix. However, the optimum concentration of GO requires further research and discussion.