Receptor Activator Of Nuclear Factor-κ Research Articles

The HLA-B27 Transgenic Rat, a Model of Spondyloarthritis, Has Decreased Bone Mineral Density and Increased RANKL to Osteoprotegerin mRNA Ratio

Bone metabolism in spondyloarthritis (SpA) is not well elucidated. We investigated alterations in bone in the HLA-B27 transgenic rat, a model of SpA. Femur, tibia, and lumbar vertebral bodies of disease-prone HLA-B27 transgenic, healthy HLA-B7 transgenic, and nontransgenic control rats were used for bone histomorphometric and dual energy x-ray absorptiometry (DEXA) analysis. Serum levels of type I collagen C-telopeptides (CTX), N-terminal propeptide of type I procollagen (P1NP), and osteocalcin, as well as receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG), were measured. RNA was isolated from the bone tissue of the femura to analyze gene expression of RANKL, OPG, and osteocalcin. Histomorphometric analysis indicated a significant decrease in bone volume as well as trabecular number and thickness in the HLA-B27 rats. Trabecular separation was increased. Numbers of osteoblasts, osteoclasts, and osteoid volume were not altered significantly. The decrease in bone mineral density was confirmed using DEXA. Levels of RANKL mRNA were significantly increased in the bone tissue of HLA-B27 transgenic rats, resulting in an increased RANKL to OPG ratio. Osteocalcin mRNA expression was also significantly elevated in bone of HLA-B27 rats. Serum levels of CTX, RANKL, OPG, P1NP, and osteocalcin did not differ significantly. Our data indicate that, similarly to SpA in humans, HLA-B27 transgenic rats show a reduced bone mass, and suggest an involvement of the RANKL/OPG system in the mechanism of bone loss in this disease. This model may be adequate to study osteoporosis in SpA.

Antibodies to receptor activator of nuclear factor-κ B ligand (RANKL)

Patent WO02095012A1 claims for the development of antibodies against receptor activator of nuclear factor-κ B ligand (RANKL) and immunologically functional fragments that neutralize RANKL. These molecules can be used to detect RANKL in biological samples, allowing the identification of pathological conditions in which RANKL alteration contributes to their pathophysiology. The use of anti-RANKL antibodies is of high importance in the treatment of bone disorders characterized by the stimulation of osteoclast function and subsequent bone loss. Postmenopausal and steroid-induced osteoporosis, myeloma bone disease, cancer bone metastases with lytic lesions and bone loss due to rheumatoid disorders (including rheumatoid arthritis) are candidates for anti-RANKL therapy, as RANKL is implicated in their pathogenesis.

Recent developments in the management of postmenopausal osteoporosis with bisphosphonates: enhanced efficacy by enhanced compliance

Bisphosphonates are the current mainstay of treatment for postmenopausal osteoporosis. Although daily oral dosing is effective, it is associated with poor compliance, partly because of the pre and postdose fasting and posture requirements. This negatively impacts treatment outcomes, leading to a reduced clinical benefit. Improved, yet still suboptimal adherence has been noticed with less frequent bisphosphonate dosing e.g. once-weekly and once-monthly oral regimens. The recently approved quarterly intravenous (i.v.) injection regimen of ibandronate and yearly i.v. infusion of zoledronic acid are attractive options in the management of postmenopausal osteoporosis. These regimens may assure quarterly and year long compliance.

Expression of the melatonin receptor (MT) 1 in benign and malignant human bone tumors

The beneficial effects of melatonin on bone homeostasis have been shown in various diseases. As this indoleamine causes dose-dependent modulation of bone-forming osteoblast and bone-resorbing osteoclast activities by receptor-independent and -dependent pathways, we investigated the expression of G-protein-coupled melatonin receptors (MTs) in malignant and non-malignant human bone lesions. By TaqMan polymerase chain reaction (PCR), we analyzed 30 specimens from osteosarcoma and 11 from benign bone tumors for MT1-mRNA expression. Furthermore, we determined mRNA expression levels of the osteoclast activity-stimulating receptor activator of nuclear factor-kappa B ligand (RANKL) and its counterpart osteoprotegerin (OPG). Although mean MT1-mRNA levels were similar (P = 0.596) in malignant (4.39 +/- 4.98-fold) and benign samples (4.64 +/- 6.81-fold), the highest MT1-mRNA levels (up to 27-fold) were observed in individual osteosarcomas, particularly, in two specimens of patients with local recurrence of the tumor. Moreover, mean RANKL- and OPG-mRNA levels were similar in malignant and benign specimens (RANKL: 7.38 +/- 9.61-fold versus 3.57 +/- 3.11-fold, P = 0.207; OPG: 23.45 +/- 32.76 versus 8.07 +/- 7.23-fold, P = 0.133). Again, highest RANKL- and OPG-mRNA levels (up to 41- and 160-fold, respectively) were observed in individual osteosarcomas. Expression of MT1-mRNA was confirmed in two human osteosarcoma cell lines (HOS, MG63). High expression levels of MT1-mRNA together with low OPG-mRNA were found in both osteosarcoma cell lines, while in normal human osteoblasts and bone marrow stromal cells, high OPG-mRNA levels were associated with low MT1-mRNA levels. These data on the abundant expression of MT1-mRNA in human bone tumors and osteosarcoma cells lines suggest an important role for MT1 in bone pathology.

Immunohistochemical analysis of low-grade and high-grade prostate carcinoma: relative changes of parathyroid hormone-related protein and its parathyroid hormone 1 receptor, osteoprotegerin and receptor activator of nuclear factor-kB ligand

Aim: To investigate multiple bone cytokines produced by prostate carcinoma (PCa) as a novel strategy to differentiate potential aggressiveness in localised PCa using immunohistochemical analysis. Methods: A total of 47...

Serum Osteoprotegerin and Receptor Activator of Nuclear Factor-κ B Ligand as Indicators of Disturbed Osteoclastogenesis in Patients With Prostate Cancer

We evaluated the behavior and diagnostic usefulness of the osteoclastogenesis proteins osteoprotegerin and receptor activator of nuclear factor-kappaB ligand (RANKL) in the serum of patients with prostate cancer (PCa). Serum osteoprotegerin and RANKL were retrospectively measured in 117 patients with prostate cancer, including 39 with stage pN0M0, 34 with stage pN1M0 and 44 with bone metastases, in 35 presumably healthy men and in 35 patients with benign prostatic hyperplasia (BPH). The association of these components with clinical data (tumor stage and grade) and receiver operating characteristics curves compared with the bone formation marker alkaline phosphatase and bone resorption marker crosslaps (cross-linked C-terminal telopeptides of type I collagen) were calculated. Osteoprotegerin was increased in patients with bone metastases, while those with localized cancer or lymph node metastases had values similar to those in presumably healthy controls and patients with BPH. RANKL did not differ among the control, BPH and PCa subgroups. Thus, the ratio of osteoprotegerin-to-RANKL showed behavior similar to that of osteoprotegerin. Osteoprotegerin and RANKL did not show any significant correlation with tumor stage, histological tumor grade, total prostate specific antigen, alkaline phosphatase activity or crosslaps. ROC analysis data proved that osteoprotegerin had a better diagnostic accuracy than alkaline phosphatase or crosslaps for detecting bone metastases in PCa cases. Serum osteoprotegerin but not RANKL indicates disturbed osteoclastogenesis in patients with PCa and bone metastatic spread. It could be used as a marker for bone metastases.