Interleukin-1ß as emerging therapeutic target in hematological malignancies and potentially in their complications.

Interleukin-1ß (IL-1ß) is a pleiotropic cytokine that exerts multiple roles in both physiological and pathological conditions. It is produced by different cell subsets, and drives a wide range of inflammatory responses in numerous target cells. Enhanced IL-1ß signaling is a common event in patients of hematological malignancies. Recent body of evidence obtained in preclinical models shows the pathogenic role of these alterations, and the promising therapeutic value of IL-1 targeting. In this review, we further highlight a potential contribution of IL-1ß linking to complications and autoimmune disease that should be investigated in future studies. Hence, drugs that target IL-1 may be helpful to improve outcome or reduce morbidity in patients. Some of them are FDA-approved, and used efficiently against autoimmune diseases, like IL-1 receptor antagonist. In the clinic, however, this agent seems to have limited properties. Current improved drugs will allow to determine the true potential of IL-1 and IL-1ß targeting as therapy in hematological malignancies and their related complications.

Quercitrin and taxifolin stimulate osteoblast differentiation in MC3T3-E1 cells and inhibit osteoclastogenesis in RAW 264.7 cells.

Flavonoids are natural antioxidants that positively influence bone metabolism. The present study screened among different flavonoids to identify biomolecules for potential use in bone regeneration. For this purpose, we used MC3T3-E1 and RAW264.7 cells to evaluate their effect on cell viability and cell differentiation. First, different doses of chrysin, diosmetin, galangin, quercitrin and taxifolin were analyzed to determine the optimum concentration to induce osteoblast differentiation. After 48h of treatment, doses ≥100µM of diosmetin and galangin and also 500µM taxifolin revealed a toxic effect on cells. The same effect was observed in cells treated with doses ≥100µM of chrysin after 14 days of treatment. However, the safe doses of quercitrin (200 and 500µM) and taxifolin (100 and 200µM) induced bone sialoprotein and osteocalcin mRNA expression. Also higher osteocalcin secreted levels were determined in 100µM taxifolin osteoblast treated samples when compared with the control ones. On the other hand, quercitrin and taxifolin decreased Rankl gene expression in osteoblasts, suggesting an inhibition of osteoclast formation. Indeed, osteoclastogenesis suppression by quercitrin and taxifolin treatment was observed in RAW264.7 cells. Based on these findings, the present study demonstrates that quercitrin and taxifolin promote osteoblast differentiation in MC3T3-E1 cells and also inhibit osteoclastogenesis in RAW264.7 cells, showing a positive effect of these flavonoids on bone metabolism.

Differential response of MC3T3-E1 and human mesenchymal stem cells to inositol hexakisphosphate.

BACKGROUND: Inositol hexakisphosphate (IP6) has been found to have an important role in biomineralization. METHODS: Because the complete mechanism of action of IP6 on osteoblasts is not fully understood and its potential use in the primary prevention of osteoporosis, we examined the direct effect of IP6 on cell viability and differentiation of MC3T3-E1 cells and on differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs). RESULTS: We show that IP6 has different effects depending on the origin of the cell target. Thus, while IP6 decreased gene expression of osteoblast markers and mineralization in MC3T3-E1 cells without negatively affecting cell viability and ALP activity, an increase in gene expression of ALP was observed in hUC-MSCs committed to the osteoblastic lineage. This increasing effect of IP6 on ALP mRNA expression levels was reversed by the addition of a selective inhibitor of IP6 kinase, suggesting that the effect of IP6 might be due through its pyrophosphorylated derivatives. Besides, Rankl mRNA levels were decreased after IP6 treatment in MC3T3-E1 cells, pointing to a paracrine effect on osteoclasts. CONCLUSION: Our results indicate that IP6 has different effects on osteoblast differentiation depending on the cell type and origin. However, further studies are needed to examine the net effect of IP6 on bone formation and its potential as novel antiosteoporosis drug.

Inositol hexakisphosphate inhibits osteoclastogenesis on RAW 264.7 cells and human primary osteoclasts.

BACKGROUND: Inoxitol hexakisphosphate (IP6) has been found to have an important role in biomineralization and a direct effect inhibiting mineralization of osteoblasts in vitro without impairing extracellular matrix production and expression of alkaline phosphatase. IP6 has been proposed to exhibit similar effects to those of bisphosphonates on bone resorption, however, its direct effect on osteoclasts (OCL) is presently unknown. METHODOLOGY/PRINCIPAL FINDINGS: The aim of the present study was to investigate the effect of IP6 on the RAW 264.7 monocyte/macrophage mouse cell line and on human primary osteoclasts. On one hand, we show that IP6 decreases the osteoclastogenesis in RAW 264.7 cells induced by RANKL, without affecting cell proliferation or cell viability. The number of TRAP positive cells and mRNA levels of osteoclast markers such as TRAP, calcitonin receptor, cathepsin K and MMP-9 was decreased by IP6 on RANKL-treated cells. On the contrary, when giving IP6 to mature osteoclasts after RANKL treatment, a significant increase of bone resorption activity and TRAP mRNA levels was found. On the other hand, we show that 1 µM of IP6 inhibits osteoclastogenesis of human peripheral blood mononuclear cells (PBMNC) and their resorption activity both, when given to undifferentiated and to mature osteoclasts. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that IP6 inhibits osteoclastogenesis on human PBMNC and on the RAW264.7 cell line. Thus, IP6 may represent a novel type of selective inhibitor of osteoclasts and prove useful for the treatment of osteoporosis.