Protective effect of vasoactive intestinal peptide on bone destruction in the collagen-induced arthritis model of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation, erosion of bone and cartilage, and severe joint pain [1-5]. Immunization of DBA-1 mice with type II collagen in complete Freund adjuvant induces the development of an inflammatory, erosive arthritis (collagen-induced arthritis (CIA) [6] accompanied by infiltration of the synovial membrane and synovial cavity as well as by extensive local bone and cartilage destruction and loss of bone mineral density [7]. This condition in mice mimics many of the clinical and pathological features of human RA. A link between the immune system and bone resorption is supported by the finding that several cytokines, such as tumor necrosis factor (TNF)α, IL-1β, IFNγ, IL-6, IL-11, and IL-17 with regulatory effects on immune function also contribute to bone homeostasis by enhancing bone resorption [8]. These cytokines have been identified in the rheumatoid synovium and could promote synovial membrane inflammation and osteocartilaginous resorption via stimulation of osteoclastic mediators [4,5,9,10].A better understanding of the pathogenesis of bone erosion in RA relates to the discovery of osteoclast-mediated bone resorption that is regulated by the receptor activator of nuclear factor-κB (RANK) ligand (RANKL) [2-5,11,12]. RANKL is expressed by a variety of cell types involved in RA, including activated T cells and synoviocytes [8]. These cells, in the presence of cytokines like TNFα and macrophage colony stimulating factor, contribute to osteoclast differentiation and activation [8]. On the other hand, osteoprotegerin (OPG), which is a member of the TNF-receptor family expressed by osteoblasts, is a decoy receptor for RANKL [11,13]. OPG inhibits bone resorption and binds with strong affinity to its ligand, RANKL, thereby preventing RANKL binding to its receptor, RANK [11,13,14].Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide of the secretin/glucagon family present in the central and