MSM Enhances GH Signaling via the Jak2/STAT5b Pathway in Osteoblast-Like Cells and Osteoblast Differentiation through the Activation of STAT5b in MSCs

Abstract

Methylsulfonylmethane (MSM) is a naturally occurring sulfur compound with well-known anti-oxidant properties and anti-inflammatory activities. But, its effects on bone are unknown. Growth hormone (GH) is regulator of bone growth and bone metabolism. GH activates several signaling pathways such as the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) pathway, thereby regulating expression of genes including insulin-like growth factor (IGF)-1. GH exerts effects both directly and via IGF-1, which signals by activating the IGF-1 receptor (IGF-1R). In this study, we investigated the effects of MSM on the GH signaling via the Jak/STAT pathway in osteoblasts and the differentiation of primary bone marrow mesenchymal stem cells (MSCs). MSM was not toxic to osteoblastic cells and MSCs. MSM increased the expression of GH-related proteins including IGF-1R, p-IGF-1R, STAT5b, p-STAT5b, and Jak2 in osteoblastic cells and MSCs. MSM increased IGF-1R and GHR mRNA expression in osteoblastic cells. The expression of MSM-induced IGF-1R and GHR was inhibited by AG490, a Jak2 kinase inhibitor. MSM induced binding of STAT5 to the IGF-1R and increased IGF-1 and IGF-1R promoter activities. Analysis of cell extracts by immunoprecipitation and Western blot showed that MSM enhanced GH-induced activation of Jak2/STAT5b. We found that MSM and GH, separately or in combination, activated GH signaling via the Jak2/STAT5b pathway in UMR-106 cells. Using siRNA analysis, we found that STAT5b plays an essential role in GH signaling activation in C3H10T1/2 cells. Osteogenic marker genes (ALP, ON, OCN, BSP, OSX, and Runx2) were activated by MSM, and siRNA-mediated STAT5b knockdown inhibited MSM-induced expression of osteogenic markers. Furthermore, MSM increased ALP activity and the mineralization of MSCs. Taken together, these results indicated that MSM can promote osteogenic differentiation of MSCs through activation of STAT5b.

Methylsulfonylmethane Induces G1 Arrest and Mitochondrial Apoptosis in YD-38 Gingival Cancer Cells

“…MSM has anti-cancer activities such as wound healing and contact inhibition, and can inhibit cell migration through the extracellular matrix in various types of cancers (14,15). Our recent study proved that MSM is able to up-regulate the expression levels of growth hormone receptor (GHR) and signal transducer and activator of transcription 5b (STAT5b) in osteoblast-like cells (16). It is also able to inhibit in vitro ketosis in mouse hepatocytes (17).…”

Methyl Sulfone Manifests Anticancer Activity in a Metastatic Murine Breast Cancer Cell Line and in Human Breast Cancer Tissue - Part 2: Human Breast Cancer Tissue

“…In the studies presented here, we show that in the presence of 200 m M methyl sulfone and when using the Ince culturing system [14] of Primaria plates and WIT-P medium, normal and cancerous human breast cells remained healthy in 3-dimensional structures for at least 3 months in culture, which is a long time to maintain most types of primary cells in culture. Joung et al [31] recently showed that methyl sulfone is nontoxic and in fact induced differentiation of primary bone marrow mesenchymal stem cells. In support of studies by Horvath et al [4] and others [3,5], we did not observe any toxicity of methyl sulfone on human breast cells, whereas normal and cancerous breast tissue cultured in the absence of methyl sulfone acquired characteristics that are associated with sick or unhealthy cells.…”

Alopecia androgénica femenina. Nuevas herramientas terapéuticas frente a los factores fisiopatológicos implicados: hormonal, oxidativo e inflamatorio

“…Origen y síntesis del metilsulfonilmetano El MSM es una molécula pequeña y de bajo peso molecular (94,13 g/mol) que forma parte en la naturaleza del llamado «ciclo del azufre» 10 . El ciclo del azufre se inicia en las algas y el plancton marino, microorganismos capaces de absorber considerables cantidades de azufre inorgánico procedente del agua de mar y convertirlo en moléculas elementales de azufre orgánico.…”

“…Una vez en la atmós-fera, los rayos ultravioleta (UV) del sol lo oxidan a dimetilsulfóxido (DMSO) y, posteriormente, a MSM. Ambos compuestos son muy solubles en agua y se concentran en el vapor atmosférico, retornando de nuevo a la tierra disueltos en la lluvia 10 . Una vez de nuevo en la tierra, el MSM es absorbido por las plantas, los árboles frutales, etc., pasando a formar parte de la alimentación de humanos y animales.…”

“…Una vez de nuevo en la tierra, el MSM es absorbido por las plantas, los árboles frutales, etc., pasando a formar parte de la alimentación de humanos y animales. Podemos encontrar concentraciones de 1-4 mg/kg de MSM en vegetales y frutas, y concentraciones de 2-5 mg/l en la leche de las vacas que se alimentan de hierba fresca 10 . Así pues, el MSM es una fuente de azufre elemental, que forma parte de nuestra dieta habitual, y que tiene la ventaja de ser muy fácilmente absorbible por su pequeño tamaño, por lo que no causa trastornos gástricos y, a igualdad de dosis, aporta mayor cantidad de azufre que los aminoácidos azufrados, tales como la cistina 8 .…”