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.Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with progressive disability, early death, increased risk of cardiovascular events, and other extra-articular manifestations that have a major impact in the quality of life of those with the disease.^1,2 The current clinical approach is to start early, after diagnosis, with aggressive therapy, followed by treatment adjustments according to changes in disease activity. However, despite the important progress in RA therapies during the past decade, several needs are still unmet. The introduction of biological agents in the early 1990s revolutionized the treatment of RA and other chronic diseases, such as inflammatory bowel disease. However, although highly effective and generally faster acting than disease-modifying anti-rheumatic drugs, many patients are not responsive, and they may also experience an increased risk of opportunistic infections. The treatments are costly.³ Thus, there is justification for exploiting novel therapies. In addition, it is also desirable to produce new therapeutics with efficacy on pain and inflammation in the joint, but also able to temper systemic complications of RA affecting the heart, lungs, muscles, and bone.¹Targeting the melanocortin (MC) system⁴ to treat RA may represent an alternative opportunity to drug discovery.⁵ Indeed, one of the melanocortin agonists, adrenocorticotropin hormone (ACTH), was shown to be effective in human RA >60 years ago⁶; researchers are showing a renewed interest.⁷ This is prompted by the fact that ACTH may afford biological actions beyond the endogenous production of cortisol,^8,9 provoking activation of peripheral MC receptors, including the melanocortin receptor 3 (MC₃). This peripheral mechanism of action of ACTH, hence independent from adrenal release of glucocorticoids, might also underlie efficacy in conditions such as proteinuric nephropathies¹⁰ and multiple sclerosis.¹¹Surmounting evidence indicates an important counterregulatory role for the melanocortin pathway during inflammation, including in the osteo-articular system, where melanocortin receptors are expressed by osteoblasts, osteoclasts, chondrocytes, fibroblasts, and immune cells. Pharmacological targeting with MC peptides leads to a variety of protective actions, including increased matrix deposition, reduced fibroblast activation, and osteoblast and chondrocyte proliferation.^12–17 In vivo, the synthetic peptide DTrp⁸–γ-melanocyte stimulating hormone (MSH; DTrp) reduces clinical signs of disease in models of inflammatory arthritis¹⁸ and urate crystal peritonitis¹⁹ by a mechanism involving MC₃. In addition, the pan-MC agonist peptide AP214 also displays anti-arthritic properties.²⁰ Recent work by Gomez-SanMiguel et al²¹ reported that the MC agonist αMSH can reduce joint inflammation, together with an improvement of extra-articular signs associated with systemic arthritis, by increasing body weight and reducing levels of muscle-wasting markers.An important clinical manifestation associated with arthritis is periodontal disease. There is epidemiological evidence associating inflammation of the gum with incidence of RA²² and, conversely, there is a higher incidence of periodontitis in RA patients.²³ Intriguingly, recent reports demonstrated the presence of alveolar bone loss, an important feature of periodontitis, in rodents during the time course of experimental models of arthritis, namely collagen- and adjuvant-induced arthritis.^24–26 Herein, we investigated the presence of alveolar bone loss in a different model of experimental arthritis: one induced by the arthritogenic K/BxN serum, which is much faster in its kinetics, and is characterized by leukocyte infiltration, synoviocyte proliferation, and cartilage and bone erosion, thus resembling many features of human RA in its active flares.^27,28 In addition, we established the involvement of the melanocortin system in the development of alveolar bone loss by using a combination of genetically engineered mice and pharmacological approaches.     

Comparative analysis of clinical, biochemical and genetic aspects associated with bone mineral density in small for gestational age children

Clinical, biochemical and genetic analysis related to bone mineral density (BMD) were carried out in children born small for gestational age (SGA) that failed to achieve postnatal catch-up growth (CUG), SGA children that completed CUG and adequate for gestational age (AGA) children. Serum IGF-I, IGF-II, IGF binding protein-3 and acid-labile subunit were lower in the SGA-CUG children as compared with the other groups. Frequencies of polymorphic variants of vitamin D receptor, estrogen receptor and collagen genes were similar among groups. The genotype 194-192 of the IGF-I gene was higher in the SGA-CUG and 196-192 was higher in the SGA+CUG group. In the SGA-CUG group, the genotype SS of the COLIA1 gene was associated with lower BMD. Therefore, IGF system and COLIA1 polymorphism distinguish prepubertal SGA-CUG children from the SGA+CUG children of the same age. Furthermore, COLIA1 polymorphism could be useful to predict osteopenia in SGA-CUG children.     

Role of Melanocortin Receptors in the Regulation of Gouty Inflammation

Gouty arthritis is a form of acute joint inflammation provoked by joint deposition of urate crystals. Although this acute pathology resolves after a few days, the marked degree of inflammation in the joint and—possibly more important to the patient—the excruciating pain it causes require proper therapeutic management. Often deemed a “poor sibling” of chronic joint pathologies such as rheumatoid arthritis and psoriatic arthritis, the increasing incidence of gout makes it a more palatable disease for novel drug discovery programs. This fact, associated with novel insights into the molecular mechanisms activated by the urate crystal deposition, is at the basis of new therapeutics under clinical development for gout, a valid example being the effective targeting of the proinflammatory cytokine interleukin-1. Here we briefly review the current status of antigout drug development and propose another target; our focus is on melanocortin receptor agonists as novel therapeutics for gout and inflammatory arthritides, a prototype of which, the adrenocorticotropic hormone, is already used in clinical settings.     

Prevalence and implications of multiple cancer screening needs among Hispanic community health center patients

Objectives  

To examine adherence rates for multiple cancer screening tests, which will inform prevention efforts in community health centers (CHCs).     

Ethnic differences in the relationship between body mass index and percentage body fat among Asian children from different backgrounds

Overweight and obesity in Asian children are increasing at an alarming rate; therefore a better understanding of the relationship between BMI and percentage body fat (%BF) in this population is important. A total of 1039 children aged 8-10 years, encompassing a wide BMI range, were recruited from China, Lebanon, Malaysia, The Philippines and Thailand. Body composition was determined using the 2H dilution technique to quantify total body water and subsequently fat mass, fat-free mass and %BF. Ethnic differences in the BMI-%BF relationship were found; for example, %BF in Filipino boys was approximately 2 % lower than in their Thai and Malay counterparts. In contrast, Thai girls had approximately 2.0 % higher %BF values than in their Chinese, Lebanese, Filipino and Malay counterparts at a given BMI. However, the ethnic difference in the BMI-%BF relationship varied by BMI. Compared with Caucasian children of the same age, Asian children had 3-6 units lower BMI at a given %BF. Approximately one-third of the obese Asian children (%BF above 25 % for boys and above 30 % for girls) in the study were not identified using the WHO classification and more than half using the International Obesity Task Force classification. Use of the Chinese classification increased the sensitivity. Results confirmed the necessity to consider ethnic differences in body composition when developing BMI cut-points and other obesity criteria in Asian children.