At a major orthopaedics meeting this weekend, researchers from the University of Rochester Medical Center are showcasing studies that merge some of the most significant modern health problems -- obesity and type 2 diabetes, infections, and joint degeneration, for example -- with the latest musculoskeletal science.
URMC presentations include a breakthrough in the development of a vaccine to prevent life-threatening methicillin-resistant staphylococcus aureus (MRSA) infections following bone and joint surgery, and the identification of a drug that might act on bone stem cells to enhance fracture healing. All are taking place at the Orthopaedic Research Society 2013 annual meeting, in San Antonio, Texas, Jan. 26 to 29.
The strong showing from the Center for Musculoskeletal Research (CMSR) continues a tradition of national leadership and innovation, said Edward M. Schwarz, Ph.D., the Burton Professor of Orthopaedics and Rehabilitation at URMC. He also directs the CMSR, which is among the top funded orthopaedics research programs in the country.
“Our emphasis on translational research in these important areas underlines our objective to tackle some of the leading causes of disability for Americans,” Schwarz said. “Reducing risks and offering solutions in each of these areas would bring enormous improvements to the field.”
Targeting MRSA, Bone Trauma
In 1998 MRSA surpassed HIV as the most deadly pathogen in the United States. And once drug-resistant staph infects the bone, it’s incurable. In this context, Schwarz and John Varrone, a graduate student, have been working for several years on a vaccine to prevent MRSA, by targeting the glucosaminidase (Gmd) protein contained in the deadly bug.
In the absence of Gmd, S. aureus cannot replicate efficiently. They’ve developed an anti-Gmd antibody that appears to offer about 50 percent protection against the bacteria in animal studies. Varrone is presenting evidence at the ORS meeting of how the immunization inhibits the bacterial growth. Meanwhile, Schwarz’s lab is using a new facility at the URMC – the Upstate Stem Cell cGMP Facility – to manufacture this anti-Gmd antibody for FDA pre-clinical and clinical trials starting this summer.
Another presentation from the Schwarz lab will describe the search for a diagnostic test to measure immunity to staph aureus. Having found that anti-Gmd antibodies are a biomarker, researchers now are correlating the clinical outcomes of infected patients with anti-Gmd measurements. They believe this is the first proposed blood test to assess immunity to the bacteria and improve diagnosis.
Yufeng Dong, M.D., Ph.D., who works in the lab of Matthew J. Hilton, Ph.D., also has identified a drug that can enhance bone repair after traumatic injury, by marshalling bone marrow-derived mesenchymal stem cells (MSCs), the earliest cells that form cartilage, bone and connective tissue. Hilton’s lab is exploring ways to control, expand and keep MSCs in a state of extended infancy, so they can be used for tissue and joint repair. The latest work takes an important step in that direction.
Obesity, Diabetes, and Bad Joints
Post-doctoral fellow Daisuke Hamada, Ph.D., discovered that the cells inside arthritic joints (fibroblast-like synovial cells) are responsive to insulin. He hypothesized that insulin may be protective against osteoarthritis, and was able to preliminarily validate the idea in mice and in human cell samples. This novel approach helps to explain the high prevalence of osteoarthritis in type 2 diabetes patients.
Another study measured the effects of a high-fat diet (60 percent of calories from fat) on tendon repair. Led by Michael David, an undergraduate student at the UR, this team developed a mouse model and compared tendon healing in lean animals and fat animals with type 2 diabetes. As predicted, healing was compromised in the fat group. Data suggests that less collagen and fewer cells at the wound site may explain the slower repair, and that insulin expression has an impact on tendon healing. Both findings are launching pads for future study.
Fourth-year medical student Matthew Brown also explored bone healing in the context of type 2 diabetes. He found that as a fracture repairs itself, more adipose tissue (fat) forms at the wound site than new bone. This suggests that when mesenchymal stem cells differentiate to become muscle, bone, cartilage, or tissue – the stem cells are being directed away from bone and toward fat production.
Although prior studies have reported similar data in type 1 diabetes, Brown said, it was important to confirm the findings in type 2 diabetes, which is far more common. More than 25 million children and adults have diabetes in the United States.
Obesity is a theme at the ORS meeting because of the rising incidence and its connection to many orthopaedic problems. Amy L. Lerner, Ph.D., associate professor of Biomedical Engineering at UR, also was invited to speak to the attendees about computational models that clarify the role of obesity as a risk factor for knee arthritis. Her lab uses special imaging techniques to better understand the biomechanics of the knee and how the distribution of forces relates to knee injury and arthritis.
Robert A. Mooney, Ph.D., an expert on the link between obesity and diabetes, and Michael J. Zuscik, Ph.D., who studies joint degeneration, served as mentors for the students and junior faculty and principal investigators on many of these studies.