osteoprotegerin and Colitis

Microfold cells (M cells) are responsible for antigen uptake to initiate immune responses in the gut-associated lymphoid tissue (GALT). Receptor activator of nuclear factor-κB ligand (RANKL) is essential for M cell differentiation. Follicle-associated epithelium (FAE) covers the GALT and is continuously exposed to RANKL from stromal cells underneath the FAE, yet only a subset of FAE cells undergoes differentiation into M cells. Here, we show that M cells express osteoprotegerin (OPG), a soluble inhibitor of RANKL, which suppresses the differentiation of adjacent FAE cells into M cells. Notably, OPG deficiency increases M cell number in the GALT and enhances commensal bacterium-specific immunoglobulin production, resulting in the amelioration of disease symptoms in mice with experimental colitis. By contrast, OPG-deficient mice are highly susceptible to Salmonella infection. Thus, OPG-dependent self-regulation of M cell differentiation is essential for the balance between the infectious risk and the ability to perform immunosurveillance at the mucosal surface.

Topics: Animals; Antibodies, Bacterial; Cecum; Cell Differentiation; Colitis; Dextran Sulfate; Disease Models, Animal; Gastrointestinal Microbiome; Homeostasis; Immunity, Mucosal; Immunoglobulin G; Intestinal Mucosa; Lymphoid Tissue; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Salmonella Infections; Salmonella typhimurium; Signal Transduction

Chronic pediatric inflammatory bowel disease (IBD) leads to lack of bone accrual, bone loss, and increased fractures. Presently there is no cure, and many IBD treatments incur negative side effects. We previously discovered treatment with exogenous irisin resolved inflammatory changes in the colon, gut lymphatics, and bone in a mild IBD rodent model. Here we assess irisin treatment in severe IBD induced via dextran sodium sulfate (DSS). Male Sprague Dawley rats (2-mo-old) were untreated (Con) or given 2% DSS in drinking water. In week two, half of each group (Con + Ir and DSS + Ir) received injections of recombinant irisin (i.p., 2x/wk). After 4 weeks, gut inflammation was associated with declines in bone mineral density and cancellous bone volume. Furthermore, elevated osteocyte TNF-α, interleukin-6, RANKL, OPG, and sclerostin corresponded with higher osteoclast surfaces and lower bone formation rate in DSS animals as well as lower ultimate load. While irisin treatment improved colon inflammation, there were no improvements in bone density or bone mechanical properties; however, irisin elevated bone formation rate, decreased osteoclast surfaces, and reduced osteocyte pro-inflammatory factors. These data highlight the negative impact of chronic gut inflammation on bone as well as the therapeutic potential of irisin as an anti-inflammatory treatment.

Topics: Animals; Biomechanical Phenomena; Body Weight; Bone and Bones; Bone Density; Bone Morphogenetic Proteins; Bone Resorption; Cancellous Bone; Colitis; Colon; Dextran Sulfate; Femur Neck; Fibronectins; Gastrointestinal Tract; Genetic Markers; Inflammation; Intestinal Mucosa; Lymphatic Vessels; Male; Osteocytes; Osteogenesis; Osteoprotegerin; RANK Ligand; Rats, Sprague-Dawley; Tibia; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha; Weight-Bearing

Topics: Animals; Carrier Proteins; Colitis; Glycoproteins; Humans; Membrane Glycoproteins; Mice; Mice, Knockout; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Proteins