SOST Gene Inhibits Osteogenesis from Adipose-Derived Mesenchymal Stem Cells by Inducing Th17 Cell Differentiation

Abstract

Background/Aims: Postmenopausal osteoporosis is considered to be an autoimmune and inflammatory process, and IL-17 plays important roles in the loss of bone mass. Sclerostin (SOST) acts as a negative regulator of bone formation by inhibiting the Wnt signaling pathway. It also is a mediator of the crosstalk between the skeletal and immune systems. However, few studies have examined the role of SOST gene in the differentiation of T helper 17 (Th17) cells. Methods: Adipose-derived stem cells (ADSCs) were isolated and transfected with pcDNA3-SOST or shSOST, and then co-cultured with CD4⁺ T cells isolated from peripheral blood mononuclear cells. The differentiation, adipogenesis, and osteogenesis of Th17 and regulatory T (Treg) cells were examined by western blot, intracellular and intranuclear staining, ELISA, and real-time quantitative PCR in this co-culture model. Results: The SOST gene promoted the secretion of IL-6 and TGF-β in ADSCs. After co-culture of ADSCs with CD4⁺ T cells, the SOST gene increased the number of CD4⁺IL-17⁺ cells and the levels of IL-17 and RORγ. However, the number of CD4⁺CD25⁺Foxp3⁺ cells was decreased, which was accompanied with a reduction of IL-10 and Foxp3 expression. In the meantime, the SOST gene inhibited the expression of COL1, OCN, and OPN, reduced the activity of alkaline phosphatase, and increased the expression of LPL and PPARγ. Furthermore, IL-17 promoted SOST gene-induced adipogenesis and increased the inhibition of osteogenesis. Conclusions: SOST promoted the differentiation of Th17 cells and reduced the differentiation of Treg cells, which exacerbated the SOST gene-induced inhibition of osteogenesis from ADSCs.

The Roles of Sclerostin in Immune System and the Applications of Aptamers in Immune-Related Research

“…Therefore, since aptamers have both inhibitory and carrier capabilities, significant clinical applications have been developed to realize their diagnostic and therapeutic potentials (68)(69)(70)(71). (11) sclerostin is necessary in inducing T helper 17 (Th17) cell differentiation, and inhibiting the differentiation of regulatory T (Treg) cells T cell (63) Multiple myeloma (MM) is characterized by abnormal accumulation of malignant plasma cells (PCs) that produce immunoglobulins (72). B cell maturation antigen (BCMA) is exclusively expressed on the surface of terminally differentiated B cells and is highly expressed on malignant PCs (73).…”

“…Although Cain et al illustrated that the absence of sclerostin results in B cell-specific defects but not the difference of cell numbers in T lymphocytes, natural killer cells, monocytes, granulocytes, and erythroid cells, You et al demonstrated that sclerostin is necessary for inducing T helper 17 (Th17) cell differentiation, which is responsible for bone resorption, through promoting the levels of IL-6 and TFG- β that are related to Th17 differentiation. In addition, sclerostin inhibits the differentiation of regulatory T (Treg) cells via reducing the expression of IL-10 and Foxp3, which play an essential role in Treg cell development ( 63 ). Given that Th17 and Treg cells plays vital roles in inflammatory bone diseases, the research provides valuable hints about the therapeutic strategy for this kind of disease involving the imbalance of Th17 and Treg cells development.…”

A network pharmacology approach to explore and validate the potential targets underlying the effect of Ginsenoside on Osteoporosis

“…Pathway in cancer shared many common signaling pathway with OP, such as Wnt signaling pathway [49], NF-κB pathway [50], PI3K-AKT-NFATc1 pathway [51] and MAPK pathway [52], etc. Sclerostin promoted Th17 cells differentiation and reduced Treg cells differentiation, which aggravate the sclerostin induced inhibition of osteogenesis [53]. Fluid shear stress that can quickly increase release of calcium from endoplasmic reticulum to induce calcium transients, plays a crucial role in osteoblast balance [54].…”

The correlation between the Th17/Treg cell balance and bone health

“…Retinoic acid-related orphan receptor-γt (RORγt) is an important transcription factor of Th17 cells that is responsible for pathological immune responses. Th17 cells not only can secrete IL-17, IL-21 and IL-22, but also can produce IFN-γ [ 28 ]. Among these cytokines, IL-17 is the most important pro-inflammatory factor.…”