Biologic Mechanisms for Pain Variation After Physical Activity in Osteoarthritis

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).

Inclusion Criteria:

Adults with Osteoarthritis:

- Age 50-80

- radiographic evidence of knee osteoarthritis (OA participants)

- self-report current non-smoker

- willing and able to walk for 30 minutes a day three days a week for six weeks at a
location that is within 30 minutes from University of Maryland Baltimore

- speaks English

Healthy Controls:

- Age 50-80

- self-reports no osteoarthritis

- self-report current non-smoker

- willing and able to walk for 30 minutes a day three days a week for six weeks at a
location that is within 30 minutes from University of Maryland Baltimore

- speaks English

Exclusion Criteria:

- unable to pass the evaluation to sign consent

- diagnosis of rheumatoid arthritis

- diagnosis of gout

- diagnosis of heart failure

- diagnosis of chronic obstructive pulmonary disease

- diagnosis of diabetes

- diagnosis of Parkinson's disease

- diagnosis of Alzheimer's disease

- diagnosis of autoimmune disease

- currently taking long-term steroid medications such as methotrexate

- weight less than 110 lbs.

- direct employee of the PI