Characterization of Subchondral Bone Modifying Treatments and Pain in a Model of Load-Induced Osteoarthritis
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Osteoarthritis (OA) is an increasingly prevalent joint disease that ranks in the top 10 for disabled years lost. OA affects the entire joint structure and causes pain and disability throughout disease progression. Aberrant subchondral bone remodeling is one facet of the disease pathology but has been shown to be a good target for new OA therapies. Pain is a clinically relevant symptom of OA, as patients do not seek treatment until their pain is affecting their daily life. Understanding how altering the abnormal subchondral bone remodeling and how pain progresses in OA will allow for better development of OA modifying treatments. To determine the effect of increasing subchondral bone formation in early stages of OA, we evaluated immediate and delayed treatment of parathyroid hormone after a single bout of damage inducing loading. Parathyroid hormone has been shown in other models to decrease cartilage damage progression and increase subchondral bone volume. In a load-induced model of PTOA, parathyroid hormone treatment does not attenuate cartilage damage progression while increasing epiphyseal bone volume. To characterize mechanisms involved in early-stage OA, we determined the cartilage and lymph node transcriptomic response at 1 week after a single bout of loading. We compared the transcriptomes of vehicle treated, PTH-treated, and ALN-treated cartilage to understand the early changes to gene expression that attenuated cartilage damage with ALN treatment at 3 and 6 weeks. The cartilage and lymph node transcriptomes with ALN treatment were distinct from vehicle and PTH treatment transcriptomes. To evaluate the development of pain-related behaviors in our load-induced OA and PTOA models, we characterized the alterations in hind limb weight distribution and mechanical hyperalgesia over time. Both load-induced OA and PTOA lead to increases in mechanical hyperalgesia, but hind limb weight distribution was altered by loading frequency and by sex. Overall, this thesis contributes to the understanding of the variations between OA and PTOA models, and provides the baseline understanding of pain related behaviors in load-induced OA and PTOA that will improve characterization of future OA treatments.