Promising bone-related therapeutic targets for rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that results in inflammation and structural destruction of the joints. A hallmark of RA pathogenesis is an imbalance of the osteoblast-osteoclast axis driven by inflammatory processes, resulting in elevated bone resorption by osteoclasts. Current therapies used to treat this disease have focused on inhibition of synovitis, but such treatments do not adequately repair damaged bone. A key pathway of osteoclast formation involves the receptor activator of nuclear factor kappaB ligand (RANKL) pathway acting on myeloid progenitor cells. The Wnt pathway has been shown to be important for the differentiation of osteoblasts from mesenchymal lineage precursors, and endogenous Wnt inhibitors, such as Dickkopf1 and sclerostin, might have important roles in osteoclast dysregulation in RA. Inhibition of the RANKL pathway, or blockade of Dickkopf1 and sclerostin, might serve to restore the osteoblast-osteoclast balance and repair bone erosion in RA joints. Such treatments, in combination with anti-inflammatory therapies, could stabilize and repair damaged joints and have the potential to be valuable additions to the armory of RA treatments.
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. ychoi3@mail.med.upenn.edu
Yongwon
Y
Choi
Joseph R
JR
Arron
Michael J
MJ
Townsend
D048868:Adaptor Proteins, Signal Transducing; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems; D005819:Genetic Markers; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D053245:RANK Ligand; C422903:SOST protein, human; C505688:TNFSF11 protein, human; D051153:Wnt Proteins