Investigating Therapeutic Strategies for Treatment of Osteoarthritis in the Knee Joint
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Date
2016-05-03
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Johns Hopkins University
Abstract
Osteoarthritis (OA) is one of the most common chronic musculoskeletal diseases of the joints and is characterized by degradation of the articular cartilage as well as hypertrophy of the bone. This leads the clinical symptoms of pain, joint stiffness, loss of mobility, and functional impairment. OA affects 33.6% of those 65 years of age and older in the United States [1]. In addition to effecting older populations, OA is also prevalent in young populations as a resultant of injuries and is termed post-traumatic OA. Current treatments of OA include non-steroidal anti-inflammatory drugs, corticosteroid injections, and hyaluronic acid injections. These therapies are targeted towards pain relief and have little to no disease-modifying activity. The following work explores three different therapeutic methods that seek to modify the disease state of OA: 1) Clearance of senescent cells (SCs) by senolytic compounds, 2) Urinary bladder matrix biomaterial injections, and 3) Hyaluronic Acid Binding Peptide (HApep)-polymer system injections.
The first therapy focuses on cellular senescence, which are known to be associated with age-related disorders such as OA. This work further explores the relationship between SC and OA and how eliminating SCs can reverse OA-related aging of the joint. It was found that SC negatively affects the chondrogenic potential of stems cells and that senescent chondrocytes can effect matrix production of healthy chondrocyte populations. Furthermore, it was found that the selective clearance of SC with Nutlin-3a senolytic increased cartilage matrix formation and reduced symptomatic pain in post-traumatic OA mouse model. The second therapy that was explored involved injection of UBM, which contains many biofactors and proteins that can encourage regeneration, into the intra-articular space. Results showed improvement in pain outcomes and also decreased amount of cartilage lesions and proteoglycan loss. Lastly, the injection of a HApep-polymer system was evaluated with the intention of increasing the retention of HA into the joint and improving the efficacy of current HA treatments and it was found that this also decreases cartilage degradation and improved pain outcomes. The three therapies presented in this thesis represent viable strategies for development of disease-modifying treatments for OA.
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Keywords
osteoarthritis, senescence, articular cartilage, synovial fluid, extracellular matrix, biomedical engineering, tissue engineering