Troy, N.Y. – As we age, our bones grow more brittle and more susceptible to fracture. Individuals with diabetes or with certain types of osteoporosis often are similarly afflicted with brittle bones.
A new study from biomedical engineers at Rensselaer Polytechnic Institute demonstrates how the compound N-phenacylthiazolium bromide, or PTB, dissolves the sugary impurities within bone tissue that cause our femurs, fibulas, and other bones to become more fragile.
Using PTB to reduce bone fragility and boost bone flexibility could lead to new strategies for preventing bone fractures in elderly individuals, as well as accelerated bone healing in patients with diabetes or osteoporosis.
“This study opens the door to new ways of thinking about the well-established, highly serious problem of brittle bones,” said Deepak Vashishth, professor in the Department of Biomedical Engineering and director of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer, who led the study. “These research findings are an important milestone on the path to our long-term goal of realizing a drug-based intervention for reducing age-related changes in bone tissue.”
Results of the study, titled “N-Phenacylthiazolium Bromide Reduces Bone Fragility Induced by Nonenzymatic Glycation,” were published online this week by the journal PLOS ONE. See the full paper here.
Rensselaer biomedical engineering graduate Brian S. Bradke, who received his undergraduate degree in 2003 and his doctoral degree earlier this year, was co-author of the paper with Vashishth.
Bones are constantly being remodeled within the human body. Cells produce acids and proteases to break down minerals and proteins in the bone, which are then resorbed into the body. At the same time, to compensate for the resorbed tissue, bones are fortified through chemical deposition and mineralization. This ongoing remodeling process slows down as cells are unable to fully remove bone containing sugary impurities called advanced glycation end-products, or AGEs, which form naturally in proteins. AGEs can modify surrounding tissue, rendering bone proteins unable to be resorbed back into the body. Over time, this leads to the bone becoming increasingly more fragile.
Bone remodeling slows with age, meaning AGEs accumulate at a great rate as we grow older. Individuals with diabetes, certain types of osteoporosis, or metabolic bone diseases are also known to have above-average AGE content. Higher concentrations of AGEs make these groups more susceptible to bone fracture and longer healing time for bone injuries.
“Once proteins in bone are modified, or cross-linked, they can no longer be digested by protease or resorbed by the body,” Vashishth said. “When this happens, the affected bones essentially freeze in time, unable to regenerate. This is a huge problem.”
The chemical PTB has previously been shown to be effective for dissolving AGEs and reducing stiffness in blood vessels for cardiovascular applications. Vashishth said his new study is the first to investigate the affect of PTB on bones.
He and Bradke applied PTB using different methods to multiple samples of human bones, taken from nine male donors between the ages of 19 and 80. The researchers tested the strength of the bones and used fluorescence to measure the amount of AGEs in the bones.
Compared to the control groups, bones treated with PTB showed a significant decrease in AGE content, as well as significant increase in flexibility, without losing calcium. The data suggests that treatment with PTB could be an effective means to reduce AGE content and decrease bone fragility caused by the modification, or cross-linking, of bone protein, Vashishth said.
“We found that PTB treatment was effective across different age groups. This is important because recent research suggests reducing the AGE content of mature bone may initiate bone turnover and promote new bone formation,” he said. “Overall, we are excited to continue investigating how PTB and its derivatives may be suitable treatments for improving bone quality.”
This research was funding in part by a special grant from the Whitaker Foundation and by the National Institutes of Health/National Institute of General Medical Sciences pre-doctoral training grant in biomolecular science and engineering at the Rensselaer CBIS.
“Vashishth is a leader in work uncovering the molecular basis of protein glycation, which has far-reaching implications in human health, including osteoporosis and other bone degenerative diseases,” said Jonathan Dordick, vice president for research and the Howard P. Isermann Professor of Chemical and Biological Engineering at Rensselaer. “Using a biomolecular strategy to combat sugar build-up in bones, Vashishth and Bradke identified a direct and tantalizingly simple therapeutic opportunity that could impact millions of patients.”