Graduate Students Health and Medicine Research Skeletal Biology

Maureen Purcell, Texas Biomedical Research Institute

In the spring of 2013 I interned at the Texas Biomedical Research Institute under a biological anthropologist whose laboratory investigates osteoarthritis (OA) using baboon skeletal remains. This internship opportunity allowed me to develop a hypothesis to further the team’s research goals relating to manifestation of OA symptoms and severity of OA.  I became part of a team of researchers that reflects the extremely interdisciplinary nature of work at Texas Biomed.

The onset of OA generally occurs around age 40, and 85% of the population has clinical or radiographic evidence of OA by the age of 75 (Sack 1995).  This pathology, also known as degenerative joint disease (DJD), generally occurs in weight-bearing joints, as opposed to all over the body as seen in rheumatoid arthritis (RA).  The changes associated with OA include osteophyte (bone spurs) formation, degradation of the cartilage, and hypertrophy (enlargement) of the joint.  Originally, researchers assumed OA was entirely tied to the “wear and tear” of the joint over time.  Recent studies have indicated that OA is multi-factorial, and researchers are uncertain what process of the degeneration begins first and why (Loeser et al. 2012).  The risk factors include genetics, lifestyle (an umbrella term that can encompass diet and activity level), and previous injuries.

OA is a significant health problem, and the epidemiology of the disease is not well understood.  While there is correlation between the bone cartilage breakdown and surrounding tissue degeneration, it is not known if these are contributing factors (Hill et al. 2007; Katz et al. 2009).  The advanced stages are recognized, but early detection and preventing the advancement of the disease is still a hurdle in the biomedical community.  Most people only see a doctor when their pain is severe, and so little is known about the early stages of OA and how each factor (calcification of cartilage, growth of osteophytes) contributes to the progression of OA.

A major advantage of utilizing the primate model in this kind of research is that the principle investigators (PIs) have the clinical history of the animal as well as the genetic information.  The animals are also kept within a controlled environment.  Therefore, variables that may not be completely controlled in a human study, such as the diet, do not confound the results.  My supervisor and the researchers in her lab also have the advantage of examining the entire knee joint from the skeletal remains.  This allows them to observe small changes in the cartilage and menisci of the knee joints that are missed with MRI and arthrogram scans.  This helps with understanding the early stages of the disease. Finally, pain is notoriously difficult to measure in humans, and even self-reported pain is siphoned through multiple cultural and personal filters that make cross-study comparisons difficult. A baboon model allows researchers to examine mobility in situations less affected by complex sociocultural factors that can confound human studies.

The discrete project assigned to me focused on ibuprofen distribution in baboons with OA.  A meta-analysis by Dijk et al. (2006) revealed that a correlation between pain severity and the progression of OA in humans was not consistently supported in the literature.  The hypothesis we were testing was that there is a correlation between severity of OA in the knee joint and ibuprofen distribution to the baboons.  The results might also reveal a relationship between the certain markers for OA and symptoms.  For example, baboons with osteophytes in a certain area might display more symptoms of OA.  It could be important to make this distinction since OA progresses differently at varying rates for each individual.  If there is no correlation, it would support previous studies that show a lack of correlation.  This would indicate that the variation in the experience of symptoms is not solely tied to sociocultural differences in how pain is perceived and reported.

The veterinarians distributed nonsteroid anti-inflammatory drugs (NSAID; e.g. ibuprofen or Advil) for animals with diagnosed OA or displaying symptoms of OA.  The documented clinical history, contained in a database called CAMP, provided information on drugs distributed, the duration, and the date for each animal.  Also in the database were medical notes about the animal’s surgeries, clinical trials, study-related tests (such as radiographs examining OA in aged animals), and general observations by the veterinarians.

To test the hypothesis I had to review the clinical history (held in the CAMP database) of all 600 animals included in the OA study.  For this task, I compiled an Excel spreadsheet detailing the clinical history of each animal.  I recorded the date and duration of NSAID distribution and if it was related to a diagnosis of OA in the knees.  I noted comments about limited range of motion, and other notes that might have indicated OA symptoms. For example, one clinical history detailed that the baboon had a “slow gait” and favored his right leg.  In addition to this, I also noted the diagnosis of crepitation (audible popping or cracking) in the knee joints, range of motion, confirmed diagnosis of OA, and dates of radiographs.  This would help researchers later correlate information about crepitation, range of motion, with severity of OA in the remains, as well as possible genetic signatures for those observations in OA individuals.

Although the main hypothesis was fairly straight forward, the other aspect of this task was to bring to my supervisor’s attention any other information that might affect her results.  I found that several animals in the late 1990’s received fibulae or tibiae defect implants as part of another study.  Those animals might not be appropriate to include in the general OA studies. In other words, their gait was altered artificially so that environmental influence might distort genetic contributions to OA, or their development of OA could be due to different genes that OA resulting without an obvious bone/joint injury.  Although frustrating to cut a few animals from the study, it demonstrated the value of the intern program in that careful review of records was possible so that the purity of the sample could be insured for the project.

I also had the opportunity to shadow the research staff in the laboratory when the data was collected from the animal tissues.  Multiple observations and types of data were obtained from the skeletal remains.  The meniscus was examined for tears, calcification, and overall damage by the project leader.  The tibial plateau (area of tibia that articulates with the femur in the knee joint), meniscus, and femoral condyles were photographed.  She also collected information of the degree of OA in the knee joint.  The info sheets for OA included a diagram of the femoral condyles, where she noted the area of visible OA change in the cartilage.  The severity of OA was also scored on a scale of 1-4, (1 = normal, no OA, 2 = observable loss of reflection, 3 = areas with erosion present, 4 = area of complete erosion to bone).  Synovial fluid (the fluid that lubricates the knee joint) and cartilage were also collected and preserved for each animal.  After all the data was collected, the knee joints were either preserved in a buffered 10% formalin solution or frozen for future study.

This was my first opportunity to examine a whole joint not fully skeletonized.  I could actually see the calcification of menisci and cartilage degeneration in animals with OA.  Although not always visible to the untrained eye, small “bumps” of calcified meniscal cartilage can be felt in the tissue.  Healthy cartilage looks bright white and shiny; degeneration is present when the area appears to have “dull” spots in the cartilage.  As degeneration continues, the cartilage may wear away completely in some areas, and osteophytes may be present.

When I began my internship, I worked with my supervisor on an application for a paid summer internship at Texas Biomed to conduct an osteoarthritis-related research project with her.  Though the application process was competitive, I successfully earned a spot for the summer.
In addition to furthering the activity level and OA project, I will examine the relationship between meniscus damage and OA in the knee.  This is also relevant to translational medicine since meniscal damage and OA symptoms are related but not epidemiologically understood (Pauli et al. 2011).
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