The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162. a human monoclonal antibody to RANKI,, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis. Introduction: RANKL is an essential osteoclastic differentiation and activation factor. Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind. placebo- controlled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:l ratio). AMG 162 doses were 0.01,0.03, 0.1.0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone- specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers. Results and Conclusions: Forty-nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of -81% in the 3.0 mgkg AMG 162 group compared with - 10% in the placebo group; serum NTX changes were -56% and 2%. respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to -3-fold after 4 days in the 3.0 mgkg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease >lo% on average in any group, and no subject had values below 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis. J Bone Miner Res 2004:19:1059-1066. Puhlished online on March I. 2004: doi: 10.13S9/JBMR.04030S

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1359/jbmr.2005.20.12.2274

A Single-Dose Placebo-Controlled Study of AMG 162, a Fully Human Monoclonal Antibody to RANKL, in Postmenopausal Women

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis

/pdf/receptor-activator-of-nuclear-factor-kb-ligand-and-34qwxtybhs.pdf

Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease

The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling.

Gene expression analysis of target organs might help provide new insights into the pathogenesis of autoimmune diseases. We used global gene expression profiling of minor salivary glands to identify patterns of gene expression in patients with primary Sjogren’s syndrome (pSS), a common and prototypic systemic autoimmune disease. Gene expression analysis allowed for differentiating most patients with pSS from controls. The expression of 23 genes in the IFN pathways, including two Toll-like receptors (TLR8 and TLR9), was significantly different between patients and controls. Furthermore, the increased expression of IFN-inducible genes, BAFF and IFN-induced transmembrane protein 1, was also demonstrated in ocular epithelial cells by quantitative RT-PCR. In vitro activation showed that these genes were effectively modulated by IFNs in salivary gland epithelial cells, the target cells of autoimmunity in pSS. The activation of IFN pathways led us to investigate whether plasmacytoid dendritic cells were recruited in salivary glands. These IFN-producing cells were detected by immunohistochemistry in all patients with pSS, whereas none was observed in controls. In conclusion, our results support the pathogenic interaction between the innate and adaptive immune system in pSS. The persistence of the IFN signature might be related to a vicious circle, in which the environment interacts with genetic factors to drive the stimulation of salivary TLRs.

https://www.pnas.org/content/pnas/103/8/2770.full.pdf

Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren’s syndrome

https://www.jivasupplements.org/assets/applets/Curcumin_Inhibits_Constitutive_NF-Kappa_B_Activation.pdf

Curcumin (diferuloylmethane) inhibits constitutive NF-κB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma

Primary Sjogren's syndrome (pSS) is an autoimmune disorder characterized by lymphocytic infiltration of the salivary glands. Most of the infiltrating cells are T cells, but other features of the disease include polyclonal B-cell activation, systemic production of autoantibodies, and increased risk of developing B-cell non-Hodgkin's lymphoma. Recently, a new tumour necrosis factor, the B-cell activating factor (BAFF; also known as BLyS), has been implicated in the polyclonal activation of B cells. Using immunohistochemistry, this study evaluated BAFF expression in labial salivary gland biopsies from 14 patients with pSS, 14 normal controls, and two patients with sarcoidosis. Labial salivary gland samples from seven patients with pSS, seven controls, and one patient with sarcoidosis were double-stained using indirect immunofluorescence. RT-PCR analysis was also performed on lip biopsy samples from two patients and two controls. In all 14 pSS specimens, infiltrating inflammatory cells strongly expressed BAFF protein, as did some ductal epithelial cells, but acinar cells were negative. Some B cells were present in the vicinity of the BAFF-positive cells. In the 14 normal labial salivary glands, some ductal cells were moderately positive, but acinar cells were negative. In the labial salivary glands from the two patients with sarcoidosis, infiltrating lymphocytes were not stained. BAFF mRNA expression was confirmed by RT-PCR in salivary glands from pSS patients. Double immunofluorescence revealed T cells and macrophages to be the main cell types expressing BAFF in salivary glands from pSS patients. In conclusion, BAFF may be expressed by T cells at the site of autoimmune damage and could play a role in the pathogenesis of pSS, particularly by triggering the activation of self-antigen-driven autoimmune B cells. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjögren's syndrome.

The new members of the tumour necrosis factor (TNF) receptor-ligand family, receptor activator of nuclear factor-kappaB ligand (RANKL) and its receptor RANK, play a crucial role in osteoclast differentiation and activation. An increased expression of RANKL and/or RANK may be involved in the excessive bone resorption observed in multiple myeloma (MM). We used immunohistochemistry to study RANK and RANKL expression in bone marrow (BM) biopsies obtained at diagnosis in 15 MM patients, six patients with monoclonal gammopathy of undetermined significance (MGUS) and 10 normal BM biopsies. Plasma cells were not labelled with anti-RANKL or anti-RANK antibodies. In all biopsies, RANKL was expressed in endosteal bone surface, around vessels and in cells characterized by cytoplasmic expansions. These last cells did not express CD45 and were vimentin positive, corresponding to bone marrow stromal cells. Numerous stromal cells expressed RANKL in MM and MGUS specimens, with a greater expression in MM than in MGUS. Very few cells were stained with anti-RANKL in normal BM specimens. With the anti-RANK antibody, small mononuclear cells in the bone microenvironment were positive and were identified as erythroblast cells. In conclusion, we showed that RANKL was expressed in reticular stromal cells, with a greater intensity in myeloma specimens. These results suggest that RANKL overexpressed by bone marrow stromal cells may contribute to the high rate of bone resorption observed in MM.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2002.03417.x

Jeanine Quillard

Papers

Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjögren's syndrome.

RANK (receptor activator of nuclear factor-kappaB) and RANKL expression in multiple myeloma.