Knitting a Broken Bone

NIDCR researchers show that biglycan plays a role in healing bone fractures

Biglycan helps to form blood vessels in broken bones that are healing. Black arrows point to blood vessels.
Biglycan helps to form blood vessels in broken bones that are healing. Black arrows point to blood vessels.

Thirty years ago, biglycan was thought to be merely a structural component that imparted mechanical stability to teeth, bones, muscles, cartilage, and tendons. Today, biglycan’s function is known to be far more complex, and scientists continue to publish papers about its many roles in the musculoskeletal system and beyond. Marian Young, Ph.D., chief of the Molecular Biology of Bones and Teeth Section of NIDCR’s Craniofacial and Skeletal Diseases Branch, and her team recently discovered that biglycan plays a role in the healing process of broken bones, and it may further potentiate healing by promoting the formation of nutrient-delivering blood vessels after an injury.

Young has been exploring the unique activities of biglycan and other proteins found in bones and teeth since the 1980s. In August 2012, “Building a Case for Biglycan” (Science Spotlight: Interviews with Researchers) summarized decades of NIDCR research since the discovery and naming of the biglycan molecule. For the article published recently online in advance of print in Matrix Biology, Young’s team assessed tissue samples from mouse leg fractures using x-ray, micro-CT scan, tissue staining, and gene expression studies, and they demonstrated that when broken bones started to knit back together, the level of blood vessel formation was higher in normal mice than in biglycan-deficient mice. In other words, biglycan may be necessary for blood vessel formation after a fracture.

Members of NIDCR's Molecular Biology of Bones and Teeth Section (from left): Andrew Donald, Post-bac IRTA and NIH Academy member; Marian Young, Section Chief; Tina Kilts, Research Biologist; Megan Noonan, Georgetown Masters Student Intern; Vardit Kram, Post-doc; and Azusa Maeda, Post-doc.
Andrew Donald, Marian Young, Tina Kilts, Megan Noonan, Vardit Kram, and Azusa Maeda.

Possible Surgical Applications

BMP-2 (bone morphogenetic protein-2) is a therapeutic product that oral and orthopedic surgeons use during surgery to hasten bone healing. Because BMP-2 is expensive, requires a large amount to work well, and can cause adverse effects, such as tissue swelling from inflammation and bone forming outside the intended boundary, researchers are trying to find a way to reduce the dose of BMP-2 by finding another substance to use along with it. Young believes that biglycan might be a candidate to be combined with BMP-2 in surgical applications that require the formation of bony tissue. She explained that biglycan binds to BMP-2 to make it work better, much in the same way that football players bring the football across the field toward the goal.
In late January, NIDCR-supported researchers at The University of North Carolina at Chapel Hill provided the preclinical proof of Young’s hypothesis. Their article, which was published online in advance of print in the Journal of Dental Research, demonstrated that low-dose BMP-2 combined with biglycan works as well as high-dose BMP-2 alone. The researchers removed a piece of bone that was 5 millimeters wide (which is about the size of a new pencil eraser, or 1/5 inch) from the lower jaw of each lab rat and implanted a collagen scaffold containing BMP-2 alone or in combination with biglycan into the surgical site. Two weeks later, the rats treated with low-dose BMP-2 and biglycan had new bone with a dense collagen fiber matrix that was better organized than new bone of rats treated with high-dose BMP-2 alone. By using a smaller amount of BMP-2 along with biglycan, the cost and the risk of adverse effects from BMP-2 were reduced without impacting bone quality. Young said, “I really like this new report that takes things one step further: to prove biglycan could help BMP-2 to work better.”

Mechanical Strength

Next, Young plans to compare the biomechanical strength of normal mouse bones and those that lack biglycan. After a fracture has healed, a greater force will likely be needed to bend and break normal bones than biglycan-deficient bones. She also wants to quantify the biomechanical advantage of administering biglycan as a bone-enhancing therapeutic agent.

Osteogenesis Imperfecta

One patient population that could benefit from the possible combination of BMP-2 and biglycan is the 30,000 Americans who have a rare, inherited disease known as brittle bone disease or osteogenesis imperfecta. People with osteogenesis imperfecta break bones very easily. Young speculates that someday biglycan, or similar agents, could be used to help such patients recover from bone fractures.

Reference

Last Reviewed on
February 2018