Jagged1 promotes breast cancer bone metastasis
Despite evidence supporting an oncogenic role in breast cancer, the Notch pathway’s contribution to metastasis remains unknown. The objective of this study [1] was to investigate the role of Notch signaling in the development of bone metastasis of breast cancer. The authors report that Notch ligand Jagged1 is overexpressed in metastasic tumor cells and activates the Notch signaling pathway in stromal bone cells. This activation leads to IL-6 release from osteoblasts that promotes tumor growth. In parallel, Jagged1 Notch activation in preosteoclasts stimulates differentiation and promotes osteolysis. Bone destruction is associated with the release of bone metastasis cytokine TGFβ that stimulates Jagged1 expression in bone tumor cells. Treatment with γ-secretase inhibitor reduced Jagged1-mediated bone metastasis by disrupting the Notch pathway in both stromal bone cells.
RANK mediates tumor-infiltrating regulatory T-cells stimulation of mammary cancer metastasis
Receptor activator of nuclear factor-kB (RANK)-ligand (RANKL) signaling is associated with osteoclast differentiation and bone resorption. Inhibition of this pathway by specific RANKL antibodies is an effective way to reduce bone metastases. Recent studies showed that this pathway was activated in prostate or breast cancer, although its precise mechanism is unknown. The objective of this study [1] was to investigate the source and the role of RANKL and the RANK-RANKL signaling in breast cancer pulmonary metastasis.
EP1 receptor: a negative regulator of the fracture healing process
Nearly 10% to 20% of all fractures have impaired healing, which has a marked impact on both the quality of life and the total cost of care. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to decreased bone repair in several clinical studies. NSAIDs inhibit cyclooxygenase enzymes, and these enzymes have subsequently been shown to play a critical role in bone formation and repair. The cyclooxygenase enzymes, COX-1 and COX-2, are involved in the synthesis of prostaglandins (PGs) from arachidonic acid. While COX-1 is constitutively expressed and plays a largely homeostatic role in bone, COX-2 expression is induced by mitogens and inflammatory cytokines to upregulate PG synthesis during repair, inflammation, or tumorigenesis. COX-2−/− mice have reduced callus formation, delayed chondrogenesis, and impaired endochondral bone formation. The major downstream product of COX-2, prostaglandin E2, regulates bone formation. PGE2 has four different receptor subtypes (EP1 through EP4), each of which exerts different effects on bone. EP2 and EP4 induce bone formation through the protein kinase A (PKA) pathway, whereas EP3 inhibits bone formation. However, the effect of EP1 receptor signaling during bone formation remains unclear.
Older men with low serum IGF-1 have an increased risk of incident fractures
Osteoporosis-related fractures constitute a major health concern not only in women but also in men. Insulin-like growth factor 1 (IGF-1) is a key determinant of bone mass, but the association between serum IGF-1 and incident fractures in men remains unclear. The aim of a recent study [1] was to evaluate the predictive value of serum IGF-1 for fracture risk in men. Older men (n=2902, mean age of 75 years) participating in the prospective, population-based Osteoporotic Fractures in Men (MrOS) Sweden study were followed for a mean of 3.3 years. Serum IGF-1 was measured at baseline by radioimmunoassay. Fractures occurring after the baseline visit were validated.
Overexpression of secreted frizzled-related protein 1 inhibits bone formation and attenuates parathyroid hormone bone anabolic effects
The Wnt signaling regulates many aspects of cell growth, differentiation, and death during pre- and postnatal periods, and is important for bone homeostasis. Wnt/β-catenin signaling promotes osteoblast differentiation from mesenchymal stem cells (MSCs). In differentiated osteoblasts, β-catenin signaling favours osteoprotegerin production which negatively controls osteoclast formation and subsequent bone resorption. Similarly to other growth factors, the Wnt pathway is tightly regulated by secreted or intracellular inhibitors such as secreted frizzled-related proteins (sFRPs). In vertebrates, the sFRPs consist of 7 members (sFRP1 to sFRP5, crescent and sizzled) and contain a frizzled (Fz)-related cysteine-rich domain that can bind to the Wnt proteins, thus preventing Wnt/receptor activation. Overexpression of sFRP1 in human osteoblasts accelerates osteoblast and osteocyte death. Conversely, sFRP1 deletion in mice results in resistance to age-related bone loss, decrease of osteoblast and osteocyte apoptosis, and decrease in bone anabolic response to parathyroid hormone (PTH). Thus, sFRP1 may be a potential target to control Wnt pathway and thus, bone formation.
 Download here the slide set presented by Prof. Friedlander, on Thursday, November 10th. |
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