Interleukin-4 Cellular Gene Therapy and Osteoprotegerin Decrease Inflammation-Associated Bone Resorption in Collagen-Induced Arthritis

To evaluate the respective action of IL-4, an anti-inflammatory cytokine, and OPG, an inhibitor of bone resorption, on the inflammatory process and the associated bone resorption in collagen-induced arthritis (CIA). After CIA induction, DBA/1 mice were treated with OPG or with IL-4 DBA/1 transfected fibroblasts or both OPG + IL-4. CIA significantly improved in IL-4 groups. OPG had no effect on arthritis clinical scores but histologic scores were reduced in OPG, IL-4, and OPG + IL-4 groups vs. nontreated CIA mice. OPG increased significantly BMD and decreased by 45% D-pyridinolin levels. Moreover association of IL-4 and OPG exerted an additive effect of BMD and resorption marker (-68%). Production of IFN-gamma in the supernatants of spleen cells was reduced in IL-4 treated mice. OPG had a moderate effect on IFN-gamma, but potentiated the inhibitory effect of IL-4. OPG and IL-4 prevent bone loss in CIA-mice model and could have additive effects on IFN-gamma secretion.     

Osteoprotegerin reduces the loss of periarticular bone mass in primary and secondary spongiosa but does not influence inflammation in rat antigen-induced arthritis

Objective: To assess the effect of osteoprotegerin (OPG) on joint swelling, synovial inflammation and cartilage destruction, periarticular and axial bone volume, and bone turnover in rat antigen-induced arthritis (AIA). Design: Rats were treated with OPG (3 mg/kg/day) at regular intervals from day 1 to day 20 of AIA. Disease activity was evaluated by measurement of joint swelling as well as, joint inflammation and destruction by histology. Bone volume and cellular turnover parameters of secondary spongiosa of the right tibia head and the third lumbar vertebra were evaluated by histomorphometry. Periarticular bone volume of the primary spongiosa at the right tibia head was measured by linear scanning. The findings were compared with those of PBS-treated AIA and healthy animals. Result: OPG treatment did not reduce joint swelling or histological signs of inflammation. Cartilage destruction was reduced. However, this effect did not reach statistical significance . In the secondary spongiosa OPG treatment reduced the loss of periarticular bone volume. However, the latter did not reach the level of healthy controls. OPG treatment significantly reduced parameters of bone formation and bone resorption. In the primary spongiosa, OPG-treatment led to a higher amount of mineralized tissue and a greater number of trabeculae compared to PBS-treated animals with AIA or healthy controls. In the axial skeleton, OPG treatment reduced bone formation and bone resorption parameters compared to healthy animals. This treatment had no influence on bone volume. Conclusions: In periarticular bone of AIA rats, OPG treatment reduced the loss of bone volume and decreased the bone turnover, thus preventing periarticular bone destruction. OPG treatment had no influence on inflammatory process or on cartilage destruction. Received 2 June 2005; returned for revision 26 July 2005; returned for final revision 9 August 2005; accepted by M. Parnham 24 September 2005 Presented in part at the 66. Annual Meeting of the American College of Rheumatology, New Orleans, U.S.A., October 2002, and at the 25. Annual Meeting of the American Society of Bone and Mineral Research, Minneapolis, USA, September 2003 Supported by grants from the Thuringian Ministry of Science, Research and Art (B307-01025, B378-01017), the Interdisciplinary Center for Clinical Research (IZKF) Jena, and the Deutsche Forschungsgemeinschaft (Br 1372/5-1) Osteoprotegerin was generously provided by Amgen (Thousand Oaks, CA, USA). Drs. Neumann and Oelzner contributed equally to this work.     

Effect of Triptolide on Expression of Receptor Activator of Nuclear Factor-κB Ligand in Rat Adjuvant Induced Arthritis

Receptor activator of nuclear factor-kappaBligand(RANKL)promotes osteoclast formation,fusion,differentiation and activation.It plays akey role in osteoclast mediated bone erosion inrheumatoid arthritis(RA).Osteoprotegerin(OPG),as a soluble decoy receptor of RANKL,can prevent bone erosion in RA.Our previousstudies have shownthat Triptolide(TP),an activecompoundidentifiedin a traditional Chinese herb--Tripterygium wilfordii Hook F(TWHF),can ef-fectively inhibit bone destruction in ex…     

骨保护素在兔下颌牵张后新骨组织中的表达

目的 研究骨保护素（osteoprotegerin,OPG）在不同时期下颌骨牵张成骨过程中表达水平的变化,探讨其可能发挥的作用.方法在30只成年大耳白兔的一侧下颌骨前部行骨切开术,用牵引器延长一侧下颌骨4mm,分别于牵张完成后的第1,3,7,14,28天处死一组动物,取牵引区新生骨痂行组织学及OPG免疫组化染色.结果下颌牵引延长后牵引间隙均有新骨形成,免疫组化染色OPG主要定位于成骨细胞的胞浆中.其中以牵引结束的第1,7天的表达最强,以后逐渐下降,第28天仅有微弱表达.结论OPG可能在牵引成骨过程中特别是调控组织细胞应力信号传递的早期发挥重要作用.     

RANKL inhibition for the management of patients with benign metabolic bone disorders

The receptor activator of NF-κB ligand (RANKL) is a member of the TNF receptor superfamily, essential for osteoclastogenesis. It binds to its receptor activator of NF-κB on the surface of osteoclast precursors and enhances their differentiation, survival and fusion, while it activates mature osteoclasts and inhibits their apoptosis. The effects of RANKL are counteracted by osteoprotegerin (OPG), a neutralizing decoy receptor. Derangement of the balance in RANKL/OPG action is implicated in the pathophysiology of metabolic bone diseases, including osteoporosis. Current therapies used to prevent or treat metabolic bone diseases are thought to act, at least in part, through modification of the RANKL/OPG dipole. The idea of using a molecule that could specifically bind and neutralize RANKL to decrease bone resorption and subsequent bone loss is appealing. Recombinant OPG was initially tested. Denosumab, a fully human monoclonal antibody against RANKL, is a promising antiresorptive agent under investigation. It rapidly decreases bone turnover markers resulting in a significant increase in bone mineral density and reduction in fracture risk. However, because receptor activator of NF-κB activation by RANKL is also essential for T-cell growth and dendritic-cell function, inhibition of its action could simultaneously affect the immune system, leading to susceptibility in infections or malignancies.