Receptor Activator Of Nuclear Factor kappa-B Ligand Inhibitor Research Articles

The Combined Effects of RhBMP-2 and Systemic RANKL Inhibitor in Patients With Bone Density Loss Undergoing Posterior Lumbar Interbody Fusion: A Retrospective Observational Analysis With Propensity Score Matching.

The risks of nonunion and subsidence are high in patients with bone density loss undergoing spinal fusion surgery. The internal application of recombinant human bone morphogenic protein 2 (rhBMP-2) in an interbody cage improves spinal fusion; however, related complications have been reported. Denosumab, a human monoclonal antibody targeting the receptor activator of nuclear factor kappa B ligand (RANKL), hinders osteoblast differentiation and function. Therefore, this study aimed to observe the combined effect of the local application of rhBMP-2 in a lumbar cage and systemic RANKL inhibition on postoperative spinal fusion in patients with bone density loss undergoing posterior lumbar interbody fusion (PLIF). This retrospective observational study included 251 consecutive patients with spinal stenosis who underwent PLIF at a single center between 2017 and 2021. Clinical outcomes were assessed, and radiographic evaluations included lumbar flexion, extension, range of motion, and subsidence. Statistical analyses were conducted to identify the combined effect of the treatment and the subsidence and spinal fusion status. One hundred patients were included in the final analysis. Denosumab treatment significantly reduced the rate of osteolysis (p = 0.013). When denosumab was administered in combination with rhBMP-2, the fusion status remained similar; however, the incidences of postoperative osteolysis and postoperative oozing day decreased. The combined use of rhBMP-2 and RANKL inhibition in patients with bone density loss can enhance bone formation after PLIF with fewer complications than rhBMP-2 alone.

IDF21-0102 RANKL inhibitor Denosumab protects against glucolipotoxicity-induced β-cell dysfunction and apoptosis

Background: Denosumab is a human monoclonal antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL). This inhibits the binding of RANKL to RANK on osteoclasts which reduces the activity of osteoclasts and avoids bone loss, and thus increases bone density. In addition, recent studies also showed that Denosumab seems to suppress blood sugar, but the underline mechanism is still unknown. Interestingly, some studies revealed the glucose-lowering effects by Denosumab may be related to the protection of β cells.

Clinicopathologic and molecular features of denosumab-treated giant cell tumour of bone (GCTB): Analysis of 21 cases

GCTB is an osteolytic, locally-aggressive, rarely-metastasizing tumour, characterized by abundance of osteoclast-like giant cells, induced by neoplastic mononuclear cells expressing high-levels of the receptor activator of nuclear factor Kappa-B ligand (RANKL), a mediator of osteoclast activation. Although the mainstay of treatment is complete tumour removal with preservation of bone, therapy with denosumab, an inhibitor of RANKL, has been introduced for selected cases. ObjectivesDenosumab-treated GCTB (DT-GCTB) was reported to show a wide spectrum of histological changes such as depletion of osteoclast-like giant cells and intralesional bone deposition, which may lead to diagnostic difficulties. We investigated clinicopathologic and molecular features of DT-GCTB, matched with pre-therapy samples. Participants21 cases were included (13 females, 8 males), aged 15 to 64 (median, 30 years). ResultsDT-GCTB showed development of sclerotic neocortex and varying degrees of osteosclerosis radiographically. Marked depletion of giant cells, different degree of ossification, fibrosis, and proliferation of mononuclear cells was observed. Staining for H3.3G34W was positive in mononuclear cells in 19 cases (90.5%), while one negative case was positive for H3.3G34V. H3F3A G34W mutation was confirmed in 17 of 19 cases (89.5%), corresponding to nuclear staining with H3.3 G34W antibody. G34L mutation was detected in one G34W negative case, in which H3.3 G34V nuclear positive staining was observed, possibly due to cross-reaction. ConclusionsPost-therapy tumours still exhibit a similar mutation profile, while significantly differing from classic GCTB morphologically. Correlation with history of denosumab administration, awareness of features of DT-GCTB, IHC and molecular studies for histone H3 mutations are important in its assessment.

Denosumab Regulates Gut Microbiota Composition and Cytokines in Dinitrobenzene Sulfonic Acid (DNBS)-Experimental Colitis

The pro-inflammatory mediator receptor activator of nuclear factor-kappa B ligand (RANKL) plays a significant role in the development of rheumatoid arthritis; however, its role in inflammatory bowel disease is unknown. Genome-wide association meta-analysis for Crohn’s disease (CD) identified a variant near the TNFSF11 gene that encodes RANKL and CD risk allele increased expression of RANKL in specific cell lines. This study aims to elucidate if the RANKL inhibitor denosumab can reduce the severity of experimental colitis and modify the gut microbiota composition using murine dinitrobenzenesulfonic acid (DNBS)-experimental model of colitis mimicking CD. In colitic conditions, denosumab treatment significantly decreased the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α within the colonic mucosa. Moreover, colitis was accompanied by disruption of gut microbiota, and preventative treatment with denosumab modulated this disruption. Denosumab treatment also modified the alpha- and beta diversity of colonic mucosa and fecal microbiota. These results provide a rationale for considering denosumab as a future potential therapy in CD; however, more detailed experimental and clinical studies are warranted.

A Novel, Tumor-Induced Osteoclastogenesis Pathway Insensitive to Denosumab but Interfered by Cannabidiol.

Bone metabolism is strictly regulated, and impaired regulation caused by hormonal imbalances induces systemic bone loss. Local bone loss caused by tumor invasion into bone is suggested to be induced by the generation of cytokines, which affect bone metabolism, by tumor cells. The major cause of systemic and local bone losses is excess bone resorption by osteoclasts, which differentiate from macrophages by receptor activator of nuclear factor kappa-B ligand (RANKL) or tumor necrosis factor-alpha (TNF-α). We previously found a novel pathway for tumor-induced osteoclastogenesis targeting osteoclast precursor cells (OPCs). Tumor-induced osteoclastogenesis was resistant to RANKL and TNF-α inhibitors. In the present study, we confirmed that exosomes derived from oral squamous cell carcinoma (OSCC) cells induced osteoclasts from OPCs. We also showed that the depletion of exosomes from culture supernatants of OSCC cells partially interfered with osteoclastogenesis, and cannabidiol, an innoxious cannabinoid without psychotropic effects, almost completely suppressed tumor-induced osteoclastogenesis. Osteoclastogenesis and its interference by cannabidiol were independent of the expression of nuclear factor of T cell c1 (NFATc1). These results show that osteoclastogenesis induced by OSCC cells targeting OPCs is a novel osteoclastogenic pathway independent of NFATc1 expression that is partially caused by tumor-derived exosomes and suppressed by cannabidiol.

Effects of RANKL on the proliferation and apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis through regulating the NF-κB signaling pathway.

The aim of this study is to investigate the regulatory effects of receptor activator of nuclear factor-kappa B ligand (RANKL) on the proliferation and apoptosis of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), and to explore its regulatory mechanism. Synoviocytes were primarily cultured in rats of recognized collagen-induced arthritis (CIA) model. Meanwhile, they were induced into FLS models by lipopolysaccharides (LPS). All cells were divided into three groups, including blank group, model group and RANKL inhibitor group. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) in the cells were detected by enzyme-linked immunosorbent assay (ELISA). The proliferation and apoptosis of FLS were detected via 3-(4,5)-dimethylthiazol (-z-y1)-3,5-diphenytetrazoliumromide (MTT) assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted to measure the messenger ribonucleic acid (mRNA) expression levels of nuclear factor-kappa B ligand (NF-κB) and Caspase-3 in FLS. Furthermore, Western blotting was adopted to detect the protein expression levels of NF-κB and Caspase-3 in FLS. Compared with the blank group, the expression levels of TNF-α and IL-1β in the cells of the model group increased significantly. Cell proliferation rate increased significantly, whereas the cell apoptosis rate decreased remarkably in the model group. Meanwhile, the mRNA and protein levels of NF-κB and Caspase-3 in FLS were significantly up-regulated. Compared with the model group, the levels of TNF-α and IL-1β in cells of RANKL inhibitor group notably declined. Similarly, cell proliferation rate was significantly reduced, whereas the cell apoptosis rate increased significantly. Furthermore, the mRNA and protein levels of NF-κB and Caspase-3 in FLS were evidently down-regulated. RANKL inhibitors can inhibit the proliferation and promote the apoptosis of FLS in RA. In addition, its mechanism may be related to the inhibition of NF-κB signaling pathway.

Malignant Sarcomatous Transformation of Benign Giant Cell Tumor of Bone after Treatment with Denosumab Therapy: A Literature Review of Reported Cases.

Giant cell tumor of bone (GCTB) is a biologically benign and locally aggressive tumor that most often affects the epiphyseal and metaphyseal sites of long bones in the young adult population. Overexpression of receptor activator of nuclear factor kappa B ligand (RANKL) by cancerous mesenchymal stromal cells stimulates a signal transduction cascade that recruits and activates multinucleated osteoclast-like giant cells, resulting in pathologic bone resorption. Denosumab, an RANKL inhibitor that blocks the RANKL-mediated osteoclast activation, has been recently approved by the United States Food and Drug Administration (FDA) for the treatment of aggressive GCTB. Although uncommon, several studies reported drug-related malignant morphological transformation of benign GCTB following treatment with denosumab therapy. The aim of the article was to review the clinicopathological characteristics of all the reported cases of malignant sarcomatous transformation of GCTB after treatment with denosumab therapy in patients without any history of prior exposure to radiotherapy.

Inhibitory effects of sodium pentosan polysulfate on formation and function of osteoclasts derived from canine bone marrow

BackgroundSodium pentosan polysulfate (NaPPS) was testified as a chondroprotective drug in with a detailed rationale of the disease-modifying activity. This study was undertaken to determine whether anti-osteoarthritis drug, NaPPS inhibited osteoclasts (OC) differentiation and function. Canine bone marrow mononuclear cells (n = 6) were differentiated to OC by maintaining with receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) for up to 7 days with the treatment of NaPPS at concentration of 0, 0.2, 1 and 5 μg/mL. Differentiation and function of OC were accessed using tartrate-resistant acid phosphate (TRAP) staining and bone resorption assay, while monitoring actin ring formation. Invasion and colocalization patterns of fluorescence-labeled NaPPS with transcribed gene in OC were monitored. Gene expression of OC for cathepsin K (CTK), matrix metallopeptidase-9 (MMP-9), nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), c-Fos, activator protein-1(AP-1) and carbonic anhydrase II was examined using real-time PCR.ResultsSignificant inhibition of OC differentiation was evident at NaPPS concentration of 1 and 5 μg/mL (p < 0.05). In the presence of 0.2 to 5 μg/mL NaPPS, bone resorption was attenuated (p < 0.05), while 1 and 5 μg/mL NaPPS achieved significant reduction of actin ring formation. Intriguingly, fluorescence-labeled NaPPS invaded in to cytoplasm and nucleus while colocalizing with actively transcribed gene. Gene expression of CTK, MMP-9 and NFATc1 were significantly inhibited at 1 and 5 μg/mL (p < 0.05) of NaPPS whereas inhibition of c-Fos and AP-1 was identified only at concentration of 5 μg/mL (p < 0.05).ConclusionsTaken together, all the results suggest that NaPPS is a novel inhibitor of RANKL and M-CSF-induced CTK, MMP-9, NFATc1, c-Fos, AP-1 upregulation, OC differentiation and bone resorption which might be a beneficial for treatment of inflammatory joint diseases and other bone diseases associated with excessive bone resorption.

Abstract S2-04: RANK ligand as a target for breast cancer prevention in BRCA1 mutation carriers

Abstract Background: BRCA1 mutation carriers commonly undergo prophylactic mastectomy to reduce their risk of breast cancer. The precise role of chemoprevention with tamoxifen, which reduces the incidence of ER-positive breast cancer in the general population, is uncertain for BRCA1 mutation carriers, where uptake has been modest. The identification of an effective and acceptable prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1mut/+ tissue harbors an aberrant population of luminal progenitor cells and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Since Receptor Activator of Nuclear Factor-kappa B ligand (RANKL) is a key paracrine effector of progesterone signaling, and RANKL and its receptor RANK contribute to mammary tumorigenesis, we investigated a role for this pathway in the preneoplastic phase of BRCA1 mutation carriers. Methods: We explored a role for the RANK/RANKL pathway during the preneoplastic phase in freshly isolated (histologically normal) patient specimens from BRCA1 mutation carriers using several approaches. RANK and RANKL expression in breast cancer was evaluated in formalin fixed paraffin embedded (FFPE) archival sections by IHC from the kConFab and the Amgen Tissue Banks. All samples were obtained with patient consent and relevant IRB approval. A role for RANKL inhibition in attenuating tumor onset was studied using the MMTV-cre/Brca1fl/fl/p53+/– mouse model that recapitulates human basal-like breast cancer. Results: We identified two subsets of luminal progenitors (RANK+ and RANK–) in histologically normal tissue of BRCA1 mutation carriers and found that RANK+ cells are highly proliferative, exhibit grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. Moreover, high levels of RANK expression prevailed in established BRCA1-associated tumors. These data suggest that RANK+ and not RANK– progenitors are a key target population in these women. Notably, inhibition of RANKL signaling by denosumab in 3D breast organoids derived from pre-neoplastic BRCA1mut/+ tissue attenuated progesterone-induced proliferation. Furthermore, inhibition of RANKL with either the RANKL inhibitor OPG-Fc or a RANKL monoclonal antibody in a Brca1-deficient mouse model significantly curtailed mammary tumorigenesis, when compared to controls (p&amp;lt;0.001). Conclusions: Together these findings identify a targetable pathway in a putative cell of origin population in BRCA1 mutation carriers and implicate RANKL blockade as a promising breast cancer prevention strategy. Citation Format: Lindeman GJ, Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L, Lok SW, Mann GB, kConFab Consortium, Rohrbach K, Huang L-Y, Soriano R, Smyth GK, Dougall WC, Visvader JE. RANK ligand as a target for breast cancer prevention in BRCA1 mutation carriers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-04.

Effect of denosumab in giant cell tumor of bone

Giant cell tumor (GCT) of bone is a benign tumor with locally aggressive nature. The presence of mononuclear stromal cells and multinucleated giant cells is the microscopic characteristic feature of the GCT. It is an osteoclastic tumor with destruction of tumor is mediated by the receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab, a RANKL inhibitor, may reduce or eliminate tumor giant cells, the relative content of proliferative, densely cellular tumor stromal cells, replacing with nonproliferative, differentiated woven new bone. We report a case of GCT of the right distal femur in a 20-year-old female, treated with 6 cycles of denosumab as neoadjuvant therapy, which shows consolidation of the lesion and became amenable for extended curettage with phenol cauterization and cementing without going for any radical surgery shown to have very good functional outcome.

Secretomes from mesenchymal stem cells participate in the regulation of osteoclastogenesis in vitro.

The receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are novel clinically effective agents that inhibit osteoclast differentiation, function, and survival by binding to RANKL. Medication-related osteonecrosis of the jaw (MRONJ), caused as a result of treatment using denosumab, is a newly emerging type of bone necrosis, the exact pathogenesis of which is unknown. Several studies recently showed that the intravenous administration of mesenchymal stem cells (MSCs) improved the osteonecrosis of the jaw, and it was hypothesized that paracrine effects by secretomes from MSCs are the main constituent. Our aim was to investigate the effects of serum-free conditioned media from human MSCs (MSC-CM) and RANKL inhibitors on osteoclast differentiation. Cytokines included in MSC-CM were identified using the cytokine array analysis. MSC-CM was added to the culture medium of rat osteoclast precursors containing RANKL inhibitor. Osteoclast differentiation assays, immunohistochemistry, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis, and pit formation assays were performed. MSC-CM included various cytokines such as the recruitment of cell osteogenesis angiogenesis and cell proliferation. MSC-CM promoted osteoclast differentiation and expression of master regulatory transcriptional factors for osteoclastogenesis. In addition, MSC-CM showed function maintenance in osteoclasts despite the presence of RANKL inhibitors. Our findings suggest that secretomes in MSC-CM were related to the regulation of osteoclast differentiation, which may reduce the effect of RANKL inhibitors. New combinations of drugs using factors included in MSC-CM have effective therapeutic modality for treating patients with MRONJ.

Denosumab Related Osteonecrosis of the Jaw with Spontaneous Necrosis of the Soft Palate: Report of a Life Threatening Case

Bisphosphonates have been used for years in the treatment of patients with distant bony metastasis and in the prevention of osteoporosis. One of main side effects of these medications is the development of bisphosphonate related osteonecrosis of the jaw (BRONJ) in a small subset of patients. A new class of medications with a shorter half-life, known as receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, was introduced with the hopes of avoiding this side effect. However, reports of osteonecrosis of the jaw after the use of RANKL inhibitors have also been documented. We report on a patient who developed a life threatening osteonecrosis of the jaw with sepsis shortly after switching from a bisphosphonate to a RANKL inhibitor for osteoporosis treatment. This patient developed several soft tissue defects including spontaneous necrosis of the soft palate. To our knowledge this is the first time this presentation has been described.

Isoliquiritigenin Inhibits Metastatic Breast Cancer Cell-induced Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin Ratio in Human Osteoblastic Cells.

Bone destruction induced by the metastasis of breast cancer cells is a frequent complication that is caused by the interaction between cancer cells and bone cells. Receptor activator of nuclear factor kappa-B ligand (RANKL) and the endogenous soluble RANKL inhibitor, osteoprotegerin (OPG), directly play critical roles in the differentiation, activity, and survival of osteoclasts. In patients with bone metastases, osteoclastic bone resorption promotes the majority of skeletal-related events and propagates bone metastases. Therefore, blocking osteoclast activity and differentiation via RANKL inhibition can be a promising therapeutic approach for cancer-associated bone diseases. We investigated the potential of isoliquiritigenin (ISL), which has anti-proliferative, anti-angiogenic, and anti-invasive effects, as a preventive and therapeutic agent for breast cancer cell-induced bone destruction. ISL at non-toxicity concentrations significantly inhibited the RANKL/OPG ratio by reducing the production of RANKL and restoring OPG production to control levels in hFOB1.19 cells stimulated with conditioned medium (CM) of MDA-MB-231 cells. In addition, ISL reduced the expression of cyclooxygenase-2 in hFOB1.19 cells stimulated by CM of MDA-MB-231 cells. Therefore, ISL may have inhibitory potential on breast cancer-induced bone destruction.

Future of bisphosphonates and denosumab for men with advanced prostate cancer.

Prostate cancer is the most common cancer occurring in American men of all races. It is also the second leading cause of cancer death among men in the USA. Bone metastasis is a frequent occurrence in men with advanced prostate cancer, with skeletal-related events being a common complication and having negative consequences, leading to severe pain, increased health care costs, increased risk of death, and decreased quality of life for patients. Bone loss can also result from antiandrogen therapy, which can further contribute to skeletal-related events. Treatment with antiresorptive agents bisphosphonates, and the newly approved denosumab, a receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitor, has been shown to reduce the risk of skeletal-related complications and prevent treatment-induced bone loss in patients with advanced prostate cancer. This review discusses the role of antiresorptive agents bisphosphonates and RANK-L inhibitor in the current treatment of advanced prostate cancer by examining the primary literature and also focuses on the likely role of the bisphosphonates in the treatment of advanced prostate cancer in the future.

OP0088 Discovery of a novel anti-bone resorption compound, AS2690168, which inhibits osteoclastogenesis induced by receptor activator of nuclear factor-kappa B ligand (RANKL)

BackgroundRANK/RANKL signaling is the pathway of osteoclast differentiation and activation. In many bone diseases, the balance of bone formation and bone resorption is impaired. In osteoporosis, bone resorption is predominant...

Review of current literature and implications of RANKL inhibitors for oral health care providers

Bisphosphonates (BPs) were the first class of drugs commonly used to prevent skeletal-related events (SRE) in patients with osteoporosis, multiple myeloma (MM), or solid tumors with metastases to bone. A new alternative class of agents, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, are now available for use in these indications and have the potential to replace intravenous BPs. This paper presents a review of the current literature on denosumab and its association with osteonecrosis of the jaw (ONJ). Denosumab is a RANKL inhibitor that has recently been approved for the prevention of SRE for the same indications as BPs except for MM. Although the overall frequency of denosumab-related ONJ may be similar or higher than estimates of the occurrence rate of bisphosphonate-related ONJ, evidence continues to support appropriate planning and preventive care can reduce the likelihood of adverse effects, including osteonecrosis.

Denosumab: Delay of bone metastasis in men with nonmetastatic castrate-resistant prostate cancer.

In a large multicenter phase 3 randomized controlled trial published in Lancet , Smith and colleagues highlight a potential new indication for denosumab for patients with hormone refractory prostate cancer (1). Already approved for prevention of skeletal-related events in the setting of bone metastases in solid tumors (Xgeva) and prevention of androgen deprivation therapy (ADT) induced bone loss (Prolia), the authors theorized that denosumab administered prior to bone metastasis might stabilize the bone microenvironment thus delaying time to first bone metastasis. Men with castrate-resistant nonmetastatic prostate cancer treated with denosumab showed improved bone-metastasis-free survival and delayed time to first bone metastasis compared to those dosed with placebo.

The role of RANKL and MMP-9 in the bone resorption caused by ameloblastoma

Ameloblastoma, a common odontogenic tumor located in jaws, generally leads to severe damage to patient's complexion and masticatory function. To expand in jaws, ameloblastoma must have a mechanism of resorbing the surrounding bone. Our objective was to explore the bone-resorption mechanism of ameloblastoma by observing the role of Receptor activator of nuclear factor kappa B ligand (RANKL) and matrix metalloproteinase-9 (MMP-9) in the bone-resorption process. In the study, the expression of RANKL and MMP-9 in ameloblastoma was detected using immunohistochemistry (IHC) and RT-PCR. Then, co-culture system of ameloblastoma cells and bone marrow cells from neonatal rabbit was erected to observe the potential of ameloblastoma cells to induce osteoclastogenesis. Finally, the induced osteoclasts were used for in vitro bone-resorption assay. In the co-culture system and the bone-resorption assay, the selective inhibitor of RANKL and MMP-9, osteoprotegerin (OPG) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were, respectively, used for observing the role of RANKL and MMP-9. The expression of RANKL and MMP-9 in ameloblastoma was confirmed. Ameloblastoma cells were found to induce bone marrow cells from neonatal rabbit differentiate into osteoclasts with bone-resorption activity. In addition, OPG was found to, respectively, have markedly inhibitory effect on osteoclastogenesis (P<0.01), and slightly inhibitory action on bone resorption (P<0.05). Ameloblastoma cells had the potential to induce osteoclastogenesis. Moreover, RANKL played an essential role in the in vitro osteoclast formation and bone resorption induced by ameloblastoma cells.

Do RANKL inhibitors (denosumab) affect inflammation and immunity?

Receptor activator of nuclear factor kappa B ligand (RANKL) and its natural antagonist, osteoprotegerin (OPG), are, respectively, an indispensable factor and a potent inhibitor for osteoclast differentiation, activity, and survival. The development of a human monoclonal antibody to RANKL, denosumab, constitutes a novel approach to prevent fragility fractures in osteoporosis, skeletal complications of malignancy, and potentially bone erosions in rheumatoid arthritis (RA). In addition to being expressed by osteoblasts, RANKL is abundantly produced by activated T cells, and synoviocytes in RA, whereas its receptor, RANK, is also expressed by monocytes/macrophages and dendritic cells. However, in preclinical and clinical studies of RA-including patients with some degree of immunosuppression-RANKL inhibitors did not significantly alter inflammatory processes. RANKL, RANK, and OPG deficiency in murine models highlights the important role of this pathway in the development and maturation of the immune system in rodents, including functions of T and/or B cells, whereas OPG overexpression in mice and rats seems innocuous with regard to immunity. In contrast, loss-of-function mutations in humans have more limited effects on immune cells. In clinical studies, the overall rate of infections, cancer, and death was similar with denosumab and placebo. Nevertheless, the risk of severe infections and cancer in some specific tissues remains to be carefully scrutinized.

Systemic RANK-Fc protein therapy is efficacious against primary osteosarcoma growth in a murine model via activity against osteoclasts

Osteosarcoma (OS) is the most common primary malignant bone tumour, and mainly affects adolescents and young adults. Although there has been substantial improvement in management of OS with surgery and chemotherapy, further survival increase has not been achieved over the past two decades. We focused on the receptor activator of nuclear factor kappaB ligand (RANKL)-osteoclast (OCL) system as a biological target for OS. RANKL is a critical factor for OCL formation and bone resorption activity. The primary lesion in bone and ensuing metastasis in OS both require the induction of OCLs. RANK-Fc is a potent RANKL antagonist and inhibitor of OCL formation and activity. In an orthotopic model in Balb/c nu/nu mice, a twice weekly dosing regimen of 350 microg of RANK-Fc per mouse subcutaneously (n= 5) reduced lung metastasis (P > 0.05), preserved bone structure and reduced tartrate-resistant acid phosphatase (TRAP)(+) OCLs (P < 0.005) in OS-bearing bone. In vitro, RANK-Fc suppressed OCL formation (P < 0.005), bone resorption activity (P < 0.005) and RANKL-induced anti-apoptosis (P < 0.5) of OCLs.