Osteoarthritis and the Metabolic Syndrome

Rajiv Gandhi

Rajiv Gandhi is an orthopaedic surgeon at Toronto Western Hospital studying the often misunderstood link between weight loss and arthritis. "Obesity has an important causal role in osteoarthritis, but it is not simply the wear and tear on joints related to the weight of the obese subject. It’s the inflammatory and biochemical effects of obesity. Patients who lose weight from 260 to 250 pounds report a remarkable improvement in their osteoarthritis that cannot be related exclusively to the reduction in weight borne by the joint. It has also been our observation that shoulder arthritis is improved by weight reduction in obese patients, though the shoulder joint bears no weight. The pathways linking obesity to osteoarthritis lead to overlap with other problems associated with the metabolic syndrome, such as hypertension, hypercholesterolemia, diabetes and heart disease. As understanding of the pathway evolves, patient education should allow us to modify risk factors for prevention and treatment."

"Recently identified hormones from fat cells and receptors for these hormones are found inside the hip and shoulder joints that are proving important clues in the understanding of osteoarthritis."

The investigative team is focusing on hormones, pain pathways in the joint and cell death. The team is comprised of PhD scientists, laboratory technicians and numerous assistants. Raj works with Nizar Mohammed, who does translational and study design work with him.

"The metabolic picture is becoming clearer. Osteoarthritis is not a disease of cartilage alone. It affects periarticular tissues, the capsule, tendons and muscles surrounding the joint. The entire structure is diseased. The hormones affect the microvasculature, resulting in instability of the subchondral bone support structure as well as the cartilage. Everything is damaged. Naively, we postulated weight on the joint as the sole factor, but since the shoulder, a large, but non - weight bearing joint is affected by hormones derived from fat, there is clearly another explanation. Fat is not a generic component. There are many fat compartments, which vary in their influence. Intra-abdominal fat and abdominal wall fat as well as pericardial fat are more metabolically active than subcutaneous fat. Advanced glycosylation products like glycosolated hemoglobin are likely some of the damaging metabolites. They damage diabetic skin, and cause cataracts as well as affecting the cartilage and subchondral bone."

"Osteoarthritis is not one disease with one mechanism. There are 2 broad categories. Some patients have solitary manifestation in one joint, whereas others have generalized osteoarthritis involving their knees, back, hips and fingers. The pathways are related, but different. Most of our studies focus on the generalized osteoarthritis phenotype. The answer, as often, will come from careful phenotyping and pathway analysis. We are also exploring

stem cell therapy, as stem cells have strong antiinflammatory effects. We are using bone marrow derived stem cells and embryonic stem cells with April Craft in the McEwen Centre. Pluripotent cells are derived from umbilical cords and bone marrow. Bone marrow cells can be backed into a multipotent form. They can be redirected toward differentiating into heart, bone and nerve cells. Stem cells may also regenerate cartilage. The cartilage is avascular, but the subchondral bone is the key factor. Microvascular disease affects the subchondral bone, limiting the nutrition of cartilage."

The goal of the lab is to characterize the pathway between the fat cells and the joint, and ultimately to identify the entire pathway sketched in Figure 1.

Figure 1

Raj works with the bariatric surgery group at Toronto Western. They harvest visceral fat from the abdomen, which is studied in the lab and compared with fat from an independent sample of joint surgery patients.

RESEARCH ETHICS BOARD

Raj became interested in serving on the Research Ethics Board as he struggled to get protocols approved to answer the question: Why does losing only 10 pounds from 260 to 250 pounds make knee pain so much better? Taufik Valiante from Toronto Western, a neurosurgeon interested in epilepsy is the other surgical member of this board. "The Research Ethics Board is interesting. I learned methodology and I learned about industry links and the troubles associated with it. Bioethicist Kyle Anstey is a great resource."

Raj is the first medical professional in his family. He is an active golfer, and mountain biker. He enjoyed his sojourn at the Harvard School of Public Health. He and Raj Rampersaud have recently completed a qualitative study of the factors that influenced patient choice to undergo surgery.

M.M.