Biologic Mechanisms for Pain Variation After Physical Activity in Osteoarthritis
Condition: Osteoarthritis, Knee; Pain; Physical Activity; Mitochondrial Pathology
MeSH terms: Osteoarthritis; Osteoarthritis, Knee
Study type: Interventional

Summary: 
      Osteoarthritis (OA) in the knee is characterized by chronic inflammatory pain that is not
      necessarily related to the amount of joint damage. Clinical practice guidelines recommend
      physical activity (PA) for osteoarthritis pain, but most adults with OA do not engage in PA.
      One reason for this is that while PA can reduce OA related joint pain, it does not work for
      everyone. PA decreases pain sensitivity for about half of adults with OA but increases pain
      sensitivity for the other half. The investigators are hypothesizing that individual
      differences in how well cells work to make energy, inflammation, and different proteins
      available in blood cells explains who PA will work to reduce pain and who it won't among
      adults with OA. The purpose of this pilot study is to determine if blood cells' ability to
      make cellular energy, inflammation and proteins help explain the difference about who PA
      reduces activity for and who it doesn't. The investigators will compare these biologic
      factors and pain sensitivity before walking, immediately after 30 minutes of walking (i.e.
      "acute") and after six weeks of walking three times a week for 30 minutes (i.e. "long-term")
      in adults with hip or knee osteoarthritis. The investigators will also compare these results
      to adults without OA. The investigators will recruit a sample of 40 adults with radiologic
      (e.g x-ray or CT scan) evidence of hip or knee OA and 20 age/gender matched healthy adults
      without OA to address the following study aims: Aim 1: To examine the effects of a six week
      (three days/week) walking program on pain in adults with OA as compared to healthy controls.
      Aim 2: To test the cells' ability to make energy as a mechanism for variation in pain after
      "acute" and "long-term" PA in older adults with lower extremity osteoarthritis. Aim3: To test
      the role of inflammation as a mechanism for variation in pain after "acute" and "long-term"
      physical activity in adults with lower extremity osteoarthritis. Aim 4: To generate
      hypotheses regarding the role of proteomics in variation in pain after "acute" and
      "long-term" physical activity.
    

Detailed description: 
      Osteoarthritis (OA) in the knee is characterized by chronic inflammatory pain that is not
      necessarily associated with the amount of joint damage.1 Clinical practice guidelines
      recommend physical activity (PA) for osteoarthritis pain,2 but uptake of PA among adults with
      OA is very low.3 One reason for this is that while PA can reduce pain among adults with lower
      extremity OA,4,5 it does so differentially, decreasing pain sensitivity for about half of
      adults with OA but actually increasing pain sensitivity for the other half.6 Further, a
      recent meta-analysis revealed that engaging in a single type of PA (e.g. aerobic exercise or
      resistance training) reduces OA knee pain, but there was large heterogeneity in the results
      which could not be explained by age, sex, BMI, alignment in the knee, disease severity, or
      baseline pain.5 One of the goals of developing individualized PA interventions for adults
      with OA is to elucidate the mechanisms by which PA reduces OA pain and for whom PA most
      effectively diminishes the pain.

      Aerobic physical activity, such as walking, increases cellular capacity for energy generation
      (ATP production) via oxidative phosphorylation up to 2-fold by stimulating mitochondrial
      biogenesis.7,8 This phenomenon occurs not only in skeletal muscle,7 but also in brain
      cells,9,10 liver cells,9,11,12 adipose tissue,13 kidney cells,12 and leukocytes14 indicating
      that PA likely increases metabolic demand systemically. Moreover, PA is thought to create
      adaptive changes in the activity and/or abundance of proteins involved in processes related
      to mitochondrial function.8 Mitochondrial function, including energy generation through
      oxidative phosphorylation; inflammation; and mitochondrial related protein expression are key
      features in osteoarthritis15,16 and chronic inflammatory pain.17,18 Animal models of
      inflammatory pain demonstrate a cellular metabolic shift from oxidative phosphorylation to
      glycolysis in chronic inflammatory states via the pyruvate dehydrogenase kinase 2/4
      (PKD2/4)-pyruvate dehydrogenase (PDH)-lactic acid axis.19 This results in an increase in
      lactic acid production in the affected area. The ensuing acidic microenvironment amplifies
      the nociceptive response via recruitment of additional pro-algesic proinflammatory cytokines
      which "activate nociceptors and spinal glia to cause peripheral and central sensitizations,
      respectively".19 Thus, improvement in the capacity to generate ATP through oxidative
      phosphorylation, and associated reduction of glycolysis, may reduce pain sensitivity.
      However, while a large body of animal and correlational data supports a strong link between
      oxidative potential and pain outcomes, experimental evidence of cause and effect remains
      sparse, especially in humans.8

      The investigators are hypothesizing that individual differences in systemic cellular
      bioenergetic function, inflammation, and protein expression influence the effect of PA to
      reduce pain sensitivity in adults with knee OA. The purpose of this quasi-experimental pilot
      study is to test mitochondrial bioenergetics (oxidative phosphorylation, mitochondrial
      content) in platelets, inflammation (cytokines) and protein expression as mechanisms for
      variation in pain sensitivity immediately after 30 minutes of walking (i.e. "acute") and
      after six weeks of walking three times a week for 30 minutes (i.e. "long-term") in adults
      with knee osteoarthritis. The investigators will address the following specific aims and
      hypotheses in a sample of 40 adults with radiologic evidence of hip or knee OA and 20
      age/gender matched healthy controls:

      Aim 1: To examine the effects of a six week (three days/week) walking program on pain
      thresholds in adults with knee OA as compared to healthy controls H1.1: Pain sensitivity
      (Quantitative Sensory Testing) will increase in approximately 50% of adults with OA and
      decrease in approximately 50% of adults with OA after acute and long-term PA.

      H1.2: Pain sensitivity will decrease in healthy controls after acute and long-term PA.

      Aim2: To test the role of mitochondrial bioenergetics (oxidative phosphorylation,
      mitochondrial content) as a mechanism for variation in pain sensitivity after PA in older
      adults with knee OA.

      H2.1: Pain sensitivity is negatively associated with mitochondrial function (oxidative
      phosphorylation, mitochondrial content) in platelets at baseline, after acute PA and
      long-term PA H2.2: Healthy controls will have higher capacity for oxidative phosphorylation
      in platelets than OA participants.

      Aim3: To test the role of inflammation as a mechanism for variation in pain sensitivity after
      physical activity in older adults with knee OA.

      H3.1: Pain sensitivity is positively associated with increased circulating proinflammatory
      cytokines (c-reactive protein, interleukin (IL)-1, IL-1β, IL-6, IL-10, tumor necrosis factor
      (TNF)-α, PGES) at baseline, after acute and long-term PA.

      Aim 4: To generate hypotheses regarding the role of proteomics in variation in pain
      sensitivity after physical activity (immediacy following and after six weeks of walking
      program) Changes in protein expression will depend on the half-life of the protein being
      expressed which can range from minutes to days.8 Thus, it is important to examine adaptive
      changes in protein expression in both the short (minutes/day post PA) and long term
      (days/weeks between bouts of physical activity).
    

Intervention name(s): Walking
Intervention type(s): Behavioral
Intervention description(s): walking 30 minutes per day, three days/week for 6 weeks with a member of study team.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Adults with knee osteoarthritis and healthy controls will both undergo the same walking intervention. The goal is to examine basic mechanism for pain sensitivity after walking.
Masking: None (Open Label)
Primary purpose: Basic Science