Association between periodontal disease and inflammatory arthritis reveals modulatory functions by melanocortin receptor type 3

Because there is clinical evidence for an association between periodontal disease and rheumatoid arthritis, it is important to develop suitable experimental models to explore pathogenic mechanisms and therapeutic opportunities. The K/BxN serum model of inflammatory arthritis was applied using distinct protocols, and modulation of joint disruption afforded by dexamethasone and calcitonin was established in comparison to the melanocortin (MC) receptor agonist DTrp8–γ-melanocyte stimulating hormone (MSH; DTrp). Wild-type and MC receptor type 3 (MC3)-null mice of different ages were also used. There was significant association between severity of joint disease, induced with distinct protocols and volumes of the arthritogenic K/BxN serum, and periodontal bone damage. Therapeutic treatment with 10 μg dexamethasone, 30 ng elcatonin, and 20 μg DTrp per mouse revealed unique and distinctive pharmacological properties, with only DTrp protecting both joint and periodontal tissue. Further analyses in nonarthritic animals revealed higher susceptibility to periodontal bone loss in Mc3r−/− compared with wild-type mice, with significant exacerbation at 14 weeks of age. These data reveal novel protective properties of endogenous MC3 on periodontal status in health and disease and indicate that MC3 activation could lead to the development of a new genus of anti-arthritic bone-sparing therapeutics

The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice

Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C–C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C–C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3−/− and CCR1−/− mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3−/− mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3−/− and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3.FAPEMIGCAPESCNPqPRPq-UFM

In-depth characterization of congenital Zika syndrome in immunocompetent mice : antibody-dependent enhancement and an antiviral peptide therapy

Background: Zika virus (ZIKV) infection during pregnancy may cause major congenital defects, including microcephaly, ocular, articular and muscle abnormalities, which are collectively defined as Congenital Zika Syndrome. Here, we performed an in-depth characterization of the effects of congenital ZIKV infection (CZI) in immunocompetent mice. Methods: Pregnant dams were inoculated with ZIKV on embryonic day 5.5 in the presence or absence of a sub-neutralizing dose of a pan-flavivirus monoclonal antibody (4G2) to evaluate the potential role of antibody-dependent enhancement phenomenon (ADE) during short and long outcomes of CZI. Findings: ZIKV infection induced maternal immune activation (MIA), which was associated with occurrence of foetal abnormalities and death. Therapeutic administration of AH-D antiviral peptide during the early stages of pregnancy prevented ZIKV replication and death of offspring. In the post-natal period, CZI was associated with a decrease in whole brain volume, ophthalmologic abnormalities, changes in testicular morphology, and disruption in bone microarchitecture. Some alterations were enhanced in the presence of 4G2 antibody. Interpretation: Our results reveal that early maternal ZIKV infection causes several birth defects in immunocompetent mice, which can be potentiated by ADE phenomenon and are associated with MIA. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection.NRF (Natl Research Foundation, S’pore)Published versio