UA Steele Center Discovery Leads to New Understanding of Proteins’ Role in IBD-related Bone Mineral Density Loss

Two proteins play a key role in inflammatory bowel disease (IBD)-related inflammation and subsequent bone mineral loss, according to new research at the University of Arizona Steele Children’s Research Center.

Each year, more than 30,000 children are diagnosed with IBD, a painful gastrointestinal disorder. IBD is a chronic inflammation of the intestinal tract that causes fatigue, diarrhea, abdominal pain and weight loss.

The two most common forms of IBD are Crohn’s disease and ulcerative colitis. They usually strike children and young adults between the ages of 10-19.

A common complication of IBD is loss of bone mineral density. Consequently, individuals with IBD have been estimated to have a 40 percent higher risk than the general population of developing osteopenia (a condition in which bone mineral density is lower than normal) or osteoporosis later in life.

The research was led by Fayez K. Ghishan, MD, professor, head of the UA Department of Pediatrics and director of the UA Steele Center, Pawel Kiela, DVM, PhD, associate professor, and Vijayababu “Vijay” Marati Radhakrishnan, PhD, assistant scientist.

Their findings were published in the prestigious journal, Gastroenterology.

The paper, "Post-translational loss of renal TRPV5 calcium channel expression, Ca(2+) wasting, and bone loss in experimental colitis," showed that the kidneys of patients with IBD produce less of the protein Klotho, which in turn leads to reduced levels of the calcium-absorbing protein TRPV5 in the kidneys, causing calcium loss in urine.

This mechanism likely contributes to the imbalance of calcium and to IBD-associated loss of bone mineral density. 

“This study is a paradigm shift in our understanding of bone calcium metabolism in IBD,” said Dr. Ghishan. “Whereas in the past, the belief was that the higher risk of bone fractures from osteopenia or osteoporosis was related to vitamin D deficiency, we now know that isn’t necessarily the case,” Dr. Ghishan explained. “We have discovered that it is the inflammatory mediators that cause calcium loss in the kidneys, which is connected to decreased amounts of Klotho and TRPV5 proteins produced in the kidneys.”

"Our bodies are designed to maintain a steady concentration of calcium in blood. Limited intestinal absorption and renal re-absorption creates an imbalance which may lead to resorption of bone – the main calcium depot,” said Dr. Kiela. “Identifying Klotho and TRPV5 as key players in inflammation-induced calcium loss is of profound basic and clinical importance."

The results of this study point to the possibility that the Klotho protein one day could be used as supplemental therapy to treat IBD patients with osteopenia and osteoporosis.

"Our findings increase our understanding of bone loss in IBD and will help advance the care for IBD patients, because we now know what causes it," said Dr. Radhakrishnan.