Osteoarthritis (OA) is a disease associated to age or conditions that precipitate aging of articular cartilage, a post-mitotic tissue that remains functional until the failure of major homeostatic mechanisms. OA severely impacts the national health system costs and patients’ quality of life because of pain and disability. It is a whole-joint disease sustained by inflammatory and oxidative signaling pathways and marked epigenetic changes responsible for catabolism of the cartilage extracellular matrix. OA usually progresses until its severity requires joint arthroplasty. To delay this progression and to improve symptoms, a wide range of naturally derived compounds have been proposed and are summarized in this review. Preclinical in vitro and in vivo studies have provided proof of principle that many of these nutraceuticals are able to exert pleiotropic and synergistic effects and effectively counteract OA pathogenesis by exerting both anti-inflammatory and antioxidant activities and by tuning major OA-related signaling pathways. The latter are the basis for the nutrigenomic role played by some of these compounds, given the marked changes in the transcriptome, miRNome, and methylome. Ongoing and future clinical trials will hopefully confirm the disease-modifying ability of these bioactive molecules in OA patients.
Notch signaling has been identified as a critical regulator of cartilage development and homeostasis. Its pivotal role was established by both several joint specific Notch signaling loss of function mouse models and transient or sustained overexpression. NOTCH1 is the most abundantly expressed NOTCH receptors in normal cartilage and its expression increases in osteoarthritis (OA), when chondrocytes exit from their healthy “maturation arrested state” and resume their natural route of proliferation, hypertrophy, and terminal differentiation. The latter are hallmarks of OA that are easily evaluated in vitro in 2-D or 3-D culture models. The aim of our study was to investigate the effect of NOTCH1 knockdown on proliferation (cell count and Picogreen mediated DNA quantification), cell cycle (flow cytometry), hypertrophy (gene and protein expression of key markers such as RUNX2 and MMP-13), and terminal differentiation (viability measured in 3-D cultures by luminescence assay) of human OA chondrocytes. NOTCH1 silencing of OA chondrocytes yielded a healthier phenotype in both 2-D (reduced proliferation) and 3-D with evidence of decreased hypertrophy (reduced expression of RUNX2 and MMP-13) and terminal differentiation (increased viability). This demonstrates that NOTCH1 is a convenient therapeutic target to attenuate OA progression.
Conclusions:We have identified that the mobility, and the correlated activity, of the transcription factors SOX9 and RUNX2 is related to the differentiation of cells toward either the chondrogenic, osteogenic or adipogenic lineage. In addition, we observe different cell populations with different transcription factor mobility. Differentiated and undifferentiated cells could be segregated based on the mobility of the transcription factors. The population differentiated cells increased in time. To our knowledge, this is the first report of differential transcriptional dynamics of RUNX2 and SOX9 during chondrogenic, osteogenic and adipogenic differentiation of hMSCs. ; z Lab. for arthritis and bone biology, Fatima Res. Inst., Daegu, Republic of Korea; x Andong Gen. Hosp., Andong, Republic of Korea Purpose: Transglutamiase 2 (TG2) also known as tissue transglutamiase, is a calcium-dependent enzyme that has a variety of intracellular and extracellular substrates. It has been well known that TG2 increases in osteoarthritis (OA) tissue and can be used as a biomarker of OA. However, it has not been well elucidated the molecular mechanism of TG2 during the cartilage degradation in OA. Methods:The surgical destabilization of the medial meniscus (DMM) model is used to induce OA in 10-week-old male C57BL/6J mice. Primary chondrocytes were obtained from E15.5 long bones, and ZDON, a cellpermeable, peptide-based, irreversible inhibitor of TG2, was used to inhibit the function of TG2 and calcium ionophore to stimulate TG2. Results: TG2 expression was increased in articular cartilage and growth plate in surgical OA model. When treated with various growth factors, only TGFb1 increased TG2 expression of primary chondrocyte in a dosedependent manner. Intra-articular injection of specific TG2 inhibitor, ZDON, ameliorated the severity and MMP-13 expression in surgicallyinduced OA. ZDON attenuated MMP-3 and MMP-13 expression in TGFband calcium ionophore-treated chondrocytes in a Runx2-independent manner. TG2 activation by calcium ionophore induced phosphorylation of FoxO3a and ZDON decreased total FoxO3a as well as nuclear FoxO3a level. FoxO3a and TG2 were co-localized in primary chondrocytes and immunoprecipitation analysis revealed a direct interaction of FoxO3a and TG2, suggesting enhanced nuclear translocation of FoxO3a by TG2. Conclusions: our data provide an evidence of TG2 as an enhancer of FoxO3a-nuclear translocation which was responsible for the TG2dependent MMP-13 expression.
Managing soil-borne pathogens is complex due to the restriction of the most effective synthetic fungicides for soil treatment. In this study, we showed that seed priming with Jania adhaerens water-soluble polysaccharides (JA WSPs) was successful in protecting tomato plants from the soil-borne pathogens Rhizoctonia solani, Pythium ultimum, and Fusarium oxysporum under greenhouse conditions. WSPs were extracted from dry thallus by autoclave-assisted method, and the main functional groups were characterized by using FT-IR spectroscopy. WSPs were applied by seed treatment at 0.3, 0.6 and 1.2 mg/mL doses, and each pathogen was inoculated singly in a growing substrate before seeding/transplant. Overall, WSPs increased seedling emergence, reduced disease severity and increased plant development depending on the dose. Transcriptional expression of genes related to phenylpropanoid, chlorogenic acid, SAR and ISR pathways, and chitinase and β-1,3 glucanase activities were investigated. Among the studied genes, HQT, HCT, and PR1 were significantly upregulated depending on the dose, while all doses increased PAL and PR2 expression as well as β-1,3 glucanase activity. These results demonstrated that, besides their plant growth promotion activity, JA WSPs may play a protective role in triggering plant defense responses potentially correlated to disease control against soil-borne pathogens.
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