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Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor‐negative, ER − ) from four independent cohorts. RANK protein expression was more frequent in ER − tumors, where it associated with poor outcome and poor response to chemotherapy. In ER − breast cancer patient‐derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER − breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK + ER − tumors after menopause. Synopsis The analyses of RANK and RANKL expression in large cohorts of breast cancer samples and functional studies in RANK+ breast cancer patient‐derived xenografts (PDXs) revealed a key role for RANK in postmenopausal women with estrogen receptor negative (ER ‐ ) breast cancer. RANK biology and prognostic value in breast cancer is determined by ER status and menopause. RANK protein expression in tumor cells is associated with ER ‐ breast cancer and poor survival in ER ‐ and postmenopausal ER ‐ breast cancer patients. RANK protein expression in tumor cells is associated with poor survival in postmenopausal breast cancer patients independent of ER expression, tumor grade, stage and size. RANK expression associates with poor response to chemotherapy in ER ‐ breast cancer and RANKL inhibition improves response to taxanes in ER ‐ breast PDXs. Graphical Abstract The analyses of RANK and RANKL expression in large cohorts of breast cancer samples and functional studies in RANK+ breast cancer patient‐derived xenografts (PDXs) revealed a key role for RANK in postmenopausal women with estrogen receptor negative ER ‐ breast cancer.

RANKL/RANK/OPG system consists of three essential signaling molecules: i) the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), ii) the receptor activator of NF-kB (RANK), and iii) the soluble decoy receptor osteoprotegerin (OPG). Although this system is critical for the regulation of osteoclast differentiation/activation and calcium release from the skeleton, different studies have elucidated its specific role in mammary gland physiology and hormone-driven epithelial proliferation during pregnancy. Of note, several data suggest that progesterone induces mammary RANKL expression in mice and humans. In turn, RANKL controls cell proliferation in breast epithelium under physiological conditions typically associated with higher serum progesterone levels, such as luteal phase of the menstrual cycle and pregnancy. Hence, RANKL/RANK system can be regarded as a major downstream mediator of progesterone-driven mammary epithelial cells proliferation, potentially contributing to breast cancer initiation and progression. Expression of RANKL, RANK, and OPG has been detected in breast cancer cell lines and in human primary breast cancers. To date, dysregulation of RANKL/RANK/OPG system at the skeletal level has been widely documented in the context of metastatic bone disease. In fact, RANKL inhibition through the RANKL-blocking human monoclonal antibody denosumab represents a well-established therapeutic option to prevent skeletal-related events in metastatic bone disease and adjuvant therapy-induced bone loss in breast cancer. On the other hand, the exact role of OPG in breast tumorigenesis is still unclear. This review focuses on molecular mechanisms linking RANKL/RANK/OPG system to mammary tumorigenesis, highlighting pre-clinical and clinical evidence for the potential efficacy of RANKL inhibition as a prevention strategy and adjuvant therapy in breast cancer settings.

Bone homeostasis is securely controlled by the dynamic well‐balanced actions among osteoclasts, osteoblasts and osteocytes. Osteoclasts are large multinucleated cells that degrade bone matrix and involve in the bone remodelling in conjunction with other bone cells, osteoblasts and osteocytes, the completely matured form of osteoblasts. Disruption of this controlling balance among these cells or any disparity in bone remodelling caused by a higher rate of resorption by osteoclasts over construction of bone by osteoblasts results in a reduction of bone matrix including bone mineral density (BMD) and bone marrow cells (BMCs). The dominating effect of osteoclasts results in advanced risk of bone crack and joint destruction in several diseases including osteoporosis and rheumatoid arthritis (RA). However, the boosted osteoblastic activity produces osteosclerotic phenotype and weakened its action primes to osteomalacia or rickets. On the other hand, senescent osteocytes predominately progress the senescence associated secretory phenotype (SASP) and may contribute to age related bone loss. Here, we discuss an advanced level work on newly identified cellular mechanisms controlling the remodelling of bone and crosstalk among bone cells as these relate to the therapeutic targeting of the skeleton.

IntroductionIn bone tissue, bone resorption by osteoclasts and bone formation by osteoblasts are repeated continuously. Osteoclasts are multinucleated cells that derive from monocyte-/macrophage-lineage cells and resorb bone. In contrast, osteoblasts mediate osteoclastogenesis by expressing receptor activator of nuclear factor-kappa B ligand (RANKL), which is expressed as a membrane-associated cytokine. Osteoprotegerin (OPG) is a soluble RANKL decoy receptor that is predominantly produced by osteoblasts and which prevents osteoclast formation and osteoclastic bone resorption by inhibiting the RANKL–RANKL receptor interaction.Materials and MethodsIn this review, we would like to summarize our experimental results on signal transduction that regulates the expression of RANKL and OPG.ResultsUsing OPG gene-deficient mice, we have demonstrated that OPG and sclerostin produced by osteocytes play an important role in the maintenance of cortical and alveolar bone. In addition, it was shown that osteoclast-derived leukemia inhibitory factor (LIF) reduces the expression of sclerostin in osteocytes and promotes bone formation. WP9QY (W9) is a peptide that was designed to be structurally similar to one of the cysteine-rich TNF-receptortype-I domains. Addition of the W9 peptide to bone marrow culture simultaneously inhibited osteoclast differentiation and stimulated osteoblastic cell proliferation. An anti-sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) antibody inhibited multinucleated osteoclast formation induced by RANKL and macrophage colony-stimulating factor (M-CSF). Pit-forming activity of osteoclasts was also inhibited by the anti-Siglec-15 antibody. In addition, anti-Siglec-15 antibody treatment stimulated the appearance of osteoblasts in cultures of mouse bone marrow cells in the presence of RANKL and M-CSF.ConclusionsBone mass loss depends on the RANK–RANKL–OPG system, which is a major regulatory system of osteoclast differentiation induction, activation, and survival.

Aim : This study was undertaken to comprehend the effect of a combination of bovine bone graft (BBG) and propolis extract on the receptor activator of nuclear κB ligand (RANKL) and osteoprotegerin (OPG) expressions in post-extraction tooth sockets. Materials and methods : Fifty-six male Cavia Cobayas were divided into eight groups each containing seven subjects. The lower left incisor of each subject was removed prior to four different materials - polyethylene glycol (PEG), propolis extract+PEG, BBG+PEG, and propolis extract+BBG+PEG (combination) being applied to the post-extraction sockets. The laboratory animals were sacrificed at three and seven days. An immunohistochemical examination was subsequently performed to observe the expression of RANKL and OPG using a light microscope at 1000× magnification. Results : The mean expression of RANKL on the third and seventh days was the lowest in the combination group, while the mean OPG expression on those days was the highest in the combination group. The one-way ANOVA tests conducted on each group produced a p value <0.05 indicating that significant differences existed between certain groups. A Pearson’s correlation test conducted on both observation day groups highlighted the opposite correlation of RANKL and OPG. Conclusions : A combination of propolis extract and BBG effectively upregulates OPG expression and downregulates RANKL expression in the preserved post-extraction socket.

The bone is an essential organ for locomotion and protection of the body, as well as hematopoiesis and mineral homeostasis. In order to exert these functions throughout life, bone tissue undergoes a repeating cycle of osteoclastic bone resorption and osteoblastic bone formation. The osteoclast is a large, multinucleated cell that is differentiated from monocyte/macrophage lineage cells by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). RANKL transduces its signal through the signaling receptor, RANK. RANKL/RANK signaling activates NFATc1, the master regulator of osteoclastogenesis, to induce osteoclastogenic gene expression. Many types of cells express RANKL to support osteoclastogenesis depending on the biological context and the dysregulation of RANKL signaling leads to bone diseases such as osteoporosis and osteopetrosis. This review outlines the findings on osteoclast and RANKL/RANK signaling that have accumulated to date.

Osteoporosis resulting from an imbalance of bone turnover between resorption and formation is a critical health issue worldwide. Estrogen deficiency following a nature aging process is the leading cause of hormone-related osteoporosis for postmenopausal women, while glucocorticoid-induced osteoporosis remains the most common in drug-induced osteoporosis. Other medications and medical conditions related to secondary osteoporosis include proton pump inhibitors, hypogonadism, selective serotonin receptor inhibitors, chemotherapies, and medroxyprogesterone acetate. This review is a summary of the cellular and molecular mechanisms of bone turnover, the pathophysiology of osteoporosis, and their treatment. Nuclear factor-κβ ligand (RANKL) appears to be the critical uncoupling factor that enhances osteoclastogenesis. In contrast, osteoprotegerin (OPG) is a RANKL antagonist secreted by osteoblast lineage cells. Estrogen promotes apoptosis of osteoclasts and inhibits osteoclastogenesis by stimulating the production of OPG and reducing osteoclast differentiation after suppression of IL-1 and TNF, and subsequent M-CSF, RANKL, and IL-6 release. It can also activate the Wnt signaling pathway to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts rather than adipocytes. Estrogen deficiency leads to the uncoupling of bone resorption and formation; therefore, resulting in greater bone loss. Excessive glucocorticoids increase PPAR-2 production, upregulate the expression of Dickkopf-1 (DKK1) in osteoblasts, and inhibit the Wnt signaling pathway, thus decreasing osteoblast differentiation. They promote osteoclast survival by enhancing RANKL expression and inhibiting OPG expression. Appropriate estrogen supplement and avoiding excessive glucocorticoid use are deemed the primary treatment for hormone-related and glucocorticoid-induced osteoporosis. Additionally, current pharmacological treatment includes bisphosphonates, teriparatide (PTH), and RANKL inhibitors (such as denosumab). However, many detailed cellular and molecular mechanisms underlying osteoporosis seem complicated and unexplored and warrant further investigation.

Bone homeostasis is preserved by the balance of maintaining between the activity of osteogenesis and osteoclastogenesis. However, investigations for the osteoclastogenesis were hampered by considerable difficulties associated with isolating and culturing osteoclast in vivo. As the alternative, stimuli‐induced osteoclasts formation from RAW264.7 cells (RAW‐OCs) have gain its importance for extensively osteoclastogenic study of bone diseases, such as rheumatoid arthritis, osteoporosis, osteolysis and periodontitis. However, considering the RAW‐OCs have not yet been well‐characterized and RAW264.7 cells are polymorphic because of a diverse phenotype of the individual cells comprising this cell linage, and different fate associated with various stimuli contributions. Thus, in present study, we provide an overview for current knowledge of the phenotype of RAW264.7 cells, as well as the current understanding of the complicated interactions between various stimuli and RAW‐OCs in the light of the recent progress.

RANKL, the essential cue for osteoclast differentiation, is the membrane-bound factor expressed by osteoclastogenesis-supporting cells such as osteoblasts and osteocytes. In vivo evidence indicates that RANKL functions as the indispensable and irreplaceable in the program of osteoclast differentiation. The reason why RANKL plays a critical role in osteoclastogenesis is discussed from the viewpoint of the distinct signaling pathways mediated by co-stimulatory receptors and the key transcription factor NFATc1.

Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients’ quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.