Gastrointestinal inflammation triggers the expansion of a population of “bone-eating” cells, leading to bone loss, Vanderbilt researchers have discovered.
The findings suggest new therapeutic targets for reducing bone loss in disorders such as inflammatory bowel disease (IBD), said Jim Cassat, MD, PhD, associate professor of Pediatrics and senior author of the study in Cellular and Molecular Gastroenterology and Hepatology.
About 40% of patients with IBD, including ulcerative colitis and Crohn’s disease, experience bone loss and are at increased risk for fractures, noted Cassat, who is also associate professor of Pathology, Microbiology and Immunology and Biomedical Engineering.
Although a link between systemic inflammation and bone loss has been observed, specific pathologic mechanisms are not clear.
Cassat and his team have previously focused on bone infections — how bacteria get into and damage bone, and how inflammation related to infection affects bone cells. Their laboratory happens to be located next door to investigators in the Vanderbilt Digestive Diseases Research Center (VDDRC), and during hallway conversations with these colleagues, they learned about bone problems in patients with IBD.
“We had built up tools to study how inflammation from infection was triggering changes in the bone, and it didn’t take long for our research interests to expand into the study of how other forms of inflammation might impact bone,” Cassat said.
With funding support from the VDDRC pilot and feasibility program, the collaborative team began to study bone changes in established mouse models of intestinal inflammation that mimic aspects of inflammatory bowel disease in humans. The models included direct chemical injury, T cell mediated injury, and two models of gastrointestinal infection.
First author Christopher Peek, PhD, a student in the Medical Scientist Training Program, led the studies.
“We started with a simple question: Does intestinal inflammation trigger changes in bone homeostasis?” Cassat said. Using imaging and other tools, the researchers found that mice with intestinal inflammation lost substantial amounts of bone.
They discovered an increase in specific cytokines (inflammatory signaling molecules) in bone that promoted expansion of osteoclast precursor cells — cells poised to become “bone-eating” osteoclasts. The osteoclast precursors had increased expression of a co-receptor called MDL-1, which is necessary for the precursors to mature into functional osteoclasts.
The researchers found that blocking MDL-1 using a monoclonal antibody treatment in mice reduced the number of osteoclasts that formed and decreased bone loss.
“Although it’s still many, many steps removed from the clinic, these studies tell us there may be targetable mechanisms to prevent some of the bone loss that’s happening in patients with IBD,” Cassat said.
He noted that the findings may help clinicians personalize therapy for patients with IBD and bone loss by guiding the selection of biologic treatments that block cytokines associated with expansion of osteoclast precursor cells. Osteoclast precursor cells might also serve as a biomarker for patients with IBD who are more likely to develop bone disease, he said.
The findings could also apply to other inflammatory disorders, Cassat said.
“If systemic inflammation — triggered by whatever source — produces cytokines that enhance these osteoclast precursor cells, there will likely be bone loss,” he said. “And targeting this set of cells, potentially by blocking MDL-1, could be a way to tamp down on the bone loss in many inflammatory disorders.”
Other participants in the study included Caleb Ford, MD, PhD, Kara Eichelberger, PhD, Justin Jacobse, MD, Teresa Torres, Damian Maseda, PhD, Yvonne Latour, M. Blanca Piazuelo, MD, Joshua Johnson, Mariana Byndloss, DVM, PhD, Keith Wilson, MD, Jeffrey Rathmell, PhD, and Jeremy Goettel, PhD.
The research was supported by the Burroughs Wellcome Fund, Crohn’s and Colitis Foundation, National Institutes of Health (grants DK058404, CA068485, GM007347, DK120114, AI138424, AI095202, AI138932, DK123489, DK128200, DK105550), Department of Veterans Affairs, Department of Defense, United States-Israel Binational Science Foundation, and The V Foundation for Cancer Research.
