Fibrosis is presented in various physiologic and pathologic conditions of the salivary gland. Transforming growth factor beta (TGF-β) pathway has a pivotal role in the pathogenesis of fibrosis in several organs, including the salivary glands. Among the TGF-β superfamily members, TGF-β1 and 2 are pro-fibrotic ligands, whereas TGF-β3 and some bone morphogenetic proteins (BMPs) are anti-fibrotic ligands. TGF-β1 is thought to be associated with the pro-fibrotic pathogenesis of sialadenitis, post-radiation salivary gland dysfunction, and Sjögren’s syndrome. Potential therapeutic strategies that target multiple levels in the TGF-β pathway are under preclinical and clinical research for fibrosis. Despite the anti-fibrotic effect of BMPs, their in vivo delivery poses a challenge in terms of adequate clinical efficacy. In this article, we will review the relevance of TGF-β signaling in salivary gland fibrosis and advances of potential therapeutic options in the field.

The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.

Dimorphic Candida exist as commensal yeast carriages or infiltrate hyphae in the oral cavity. Here, we investigated the clinical relevance of Candida hyphae in non-pseudomembranous oral candidiasis (OC) by smears of tongue biofilms. We conducted a retrospective study of 2829 patients who had had tongue smears regardless of OC suspicion. Clinical characteristics were evaluated using a novel method of assessing hyphae. Clinical factors (moderate/severe stimulated pain, pain aggravated by stimulation, tongue dorsum appearance and initial topical antifungal use) were highly significant in the high-grade hyphae group but were statistically similar in the low-grade hyphae and non-observed hyphae group, suggesting low-grade hyphae infection as a subclinical OC state. In addition to erythematous candidiasis (EC), a new subtype named “morphologically normal symptomatic candidiasis” (MNSC) with specific pain patterns and normal tongue morphology was identified. MNSC had a significantly higher proportion of moderate and severe stimulated pain cases than EC. Low unstimulated salivary flow rate (<0.1 mL/min) was found to be a common risk factor in MNSC and EC. In non-pseudomembranous OC, pain patterns were dependent on Candida hyphae degree regardless of tongue dorsum morphology. Morphologic differences seen in high-grade hyphae infection were not associated with systemic diseases or nutritional deficiencies.

The osteogenic capabilities and biodegradability of octacalcium phosphate (OCP) composites make them unique. Despite the excellent characteristics of OCP, their use is limited due to handling difficulties. In this study, we aimed to evaluate and compare three types of OCPs (cemented OCP (C-OCP), C-OCP with collagen (OCP/Col), and synthetic OCP (S-OCP) with alginate (OCP/Alg)) versus commercially available β-tricalcium phosphate (β-TCP) regarding their potential to accelerate bone formation in defective rat tibias. The specimens with OCP composite were manufactured into 5 ​mm cubes and inserted into the segmental defects of rat tibias fixed with an external fixator. In addition, 3 ​mm-hole defects in rat tibias were evaluated to compare the graft material properties in different clinical situations. Serial X-ray studies were evaluated weekly and the tibias were harvested at postoperative 6 weeks or 8 weeks for radiologic evaluation. Histological and histomorphometric analyses were performed to evaluate the acceleration of bone formation. In the critical-defect model, OCP/Alg showed bone bridges between segmentally resected bone ends that were comparable to those of β-TCP. However, differences were observed in the residual graft materials. Most β-TCP was maintained until 8 weeks postoperatively; however, OCP/Alg was more biodegradable. In addition calcification in the β-TCP occurred at the directly contacted area between graft particles and bony ingrowth was observed in the region adjacent resected surface of tibia. In contrast, no direct bony ingrowth was observed in OCP-based materials, but osteogenesis induced from resected surface of tibia was more active. In the hole-defect model, OCP/Col accelerated bone formation. β-TCP and OCP/Alg showed similar patterns with relatively higher biodegradability. In histology, among the OCP-based materials, directly contacted new bone was formed only in OCP/Alg group. The new bone formation in the periphery area of graft materials was much more active in the OCP-based materials, and the newly formed bone showed a thicker trabecular and more mature appearance than the β-TCP group. In this study, OCP/Alg was equivalent to β-TCP in the acceleration of bone formation with better biodegradability appropriate for clinical situations in different circumstances. Our OCP/Col composite showed fast degradation, which makes it unsuitable for use in mechanical stress conditions in clinical orthopedic settings. In our research, we compared our various manufactured OCP composites to commercially available β-TCP in critical-defect rat tibia model. OCP/Col showed acceleration in hole-defect model as previous studies in dental field but in our critical-sized defect model it resorbed fast without acceleration of bony union. OCP/Alg showed matched results compared to β-TCP and relatively fast resorption so we showed market value in special clinical indication depending on treatment strategy. This is the first OCP composite study in orthopaedics with animal critical-sized tibia bone study and further study should be considered for clinical application based on this study.

Young-Jae Yee, Dawool Han, Chena Lee, Jun-Young Kim. JKAOMS 2022;48:237-41. https://doi.org/10.5125/jkaoms.2022.48.4.237