OREF grant recipient explores connection between diabetes, OA, and arthroplasty
It all started with a clinical observation. Allan L. Bucknell, MD, a professor with the University of Colorado-Denver and the Veterans Affairs (VA) Eastern Colorado Health Care System, was curious about why, after total knee arthroplasty, his diabetic patients did not fare as well as his nondiabetic patients. He wanted to know, for example, why he saw earlier aseptic prosthesis loosening in diabetic patients.

"Total knee replacement is not a benign procedure," said Dr. Bucknell. "An elusive problem in the diabetic patient population is aseptic prosthesis loosening. This may be related to poor bone formation and repair associated with the disease. In light of the rapidly increasing incidence rates of both osteoarthritis (OA) and diabetes, improvements to arthroplasty outcomes in the presence of comorbid diabetes are urgently needed."

To learn more about the connection between diabetes and OA, Dr. Bucknell collaborated with research partners Karen B. King, PhD, a biochemist and associate professor of orthopaedics, and Craig A. Hogan, MD, assistant professor of orthopaedics, at the University of Colorado-Denver and VA Eastern Colorado Health Care System to apply for Orthopaedic Research and Education Foundation (OREF) funding. They received a 2014 OREF/Goldberg Research Grant in Arthritis to research therapeutic targets that could improve arthroplasty outcomes in diabetes mellitus patients. The OREF/Goldberg grant is funded by the Dr. Victor and Mrs. Harriet Goldberg Endowment Fund.

Effects of hyperglycemia on collagen
"This research has fairly big implications," said Dr. Bucknell. "It will identify clinical targets for improving joint health and decreasing OA in those with diabetes, and for improving arthroplasty outcomes in patients with diabetes. Current thinking regarding diabetes often focuses on body mass index and adipose tissue. Although they do have large effects on joint health and arthroplasty, they are not the entire story. We hope to elucidate additional mechanisms related to diabetes that harm joint homeostasis and repair, such as chronic inflammation and hyperglycemia."

Dr. King agrees. She noted that hyperglycemia can be difficult to detect and, left unchecked, high blood glucose can have long-lasting effects on bones and joints.

"Collagen is a key structural molecule to most of the tissues in bones and joints, but collagen molecules don't turn over often, so it's a problem if they've been affected by high blood sugar," she explained. "Patients can control their diabetes, but it's possible that they could have had high blood sugar long before their diagnosis, and the effect on collagen can be long lasting. The molecules in the tissues are affected by excess sugar and that may have an effect on how well they repair postsurgically. Hyperglycemia may have already affected how their tissues behave before they need the surgery, before they started to notice pain or disability and needed a joint replacement."

Effects of diabetes on OA and arthroplasty
Dr. Bucknell and his research team's long-term objective is to identify therapeutic targets that will improve arthroplasty outcomes in the presence of comorbid type II diabetes mellitus (T2DM). The researchers hypothesize that cellular mechanisms related to diabetes increase OA severity resulting in the need for arthroplasty earlier than optimal, and also decrease bone repair, which leads to decreased arthroplasty success.

"We think that T2DM causes metabolic changes in the cells of joint tissues, leading to an impaired extracellular matrix," said Dr. Bucknell. "We further hypothesize that these metabolic mechanisms are potential targets for therapeutic intervention to improve joint health and to improve arthroplasty outcomes in the T2DM population."

With their OREF grant, the researchers aim to do the following:

• Design an animal model of diabetes and a surgical model of OA to test the hypothesis that diabetes accelerates OA progression. OA is initiated using an established in vivo surgical model called the destabilized medial meniscus (DMM) model. DMM surgery is performed on male mice of the KKAy strain, a new but well-characterized model of T2DM. The knee joints are examined histologically for the presence and severity of OA at 4, 6, and 8 weeks post-DMM surgery. A validated OA score is used to quantify severity compared to controls at each time point.
• Identify the mechanisms of T2DM-associated joint damage and T2DM-associated inhibition of postarthroplasty repair. The researchers are collecting cartilage, bone, synovial fluid, and blood serum from the animal model and arthroplasty patients with T2DM. From these tissues they take biochemical measurements of advanced glycation end-products (AGE). AGEs are proteins or lipids that become glycated as a result of exposure to sugar. When these glycated molecules bind to AGE receptors (RAGE), it is thought that pro-inflammatory genes are activated. These inflammatory molecules and tissue degradative enzymes that mediate OA will also be measured and potential therapeutic targets sought.

Potential new strategies for diabetes patients
Drs. Bucknell and King anticipate finding that mice and patients with diabetes have increased AGE-RAGE signaling and increased inflammation leading to severe OA joint pathology at earlier time points than nondiabetic controls. Initial data support this idea—for example, DMM mice experienced an increase in degradation and osteophyte activity.

The researchers are hopeful they will be able to eventually identify therapeutic targets to improve arthroplasty outcomes in the presence of comorbid diabetes mellitus. These improvements would include the development of interventions to retard OA in the diabetic population and to improve diabetic bone-prosthesis integration.

"It is possible that new strategies for identifying high-risk candidates for arthroplasty could be based on data obtained by our project," said Dr. Bucknell. "These strategies could include serum and/or synovial fluid biomarkers identified as part of the cellular mechanisms related to diabetes that affect joint homeostasis and repair."

Long-range plan
The OREF-funded study is just the first part of a comprehensive long-range plan to investigate the effects of the diabetes epidemic on OA and arthroplasty. Data obtained from this project will be used to support National Institutes of Health and/or Department of Veterans Affairs investigator-initiated grant applications to further study the effect of T2DM on the progression of OA.

"A lot of the diabetes research that has been funded is looking at other aspects of the disease, such as the pancreas, but it isn't focused on the skeleton, joints, and mobility," said Dr. King. "Now that patients with diabetes are living longer, they're being affected more by conditions of age such as OA. We want to keep them mobile."

Drs. Bucknell and King hope that the VA will back further research on how diabetes affects OA and arthroplasty, and they both said that receiving funding from OREF gave visibility to the problem Dr. Bucknell had observed in his clinic.

"I think once we get on first base with this," said Dr. Bucknell, "the VA is going to help us fund it, and it will be because of the OREF grant."

Mark Crawford is a contributing writer for OREF. He can be reached at communications@oref.org

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