Investigating Therapeutic Strategies for Treatment of Osteoarthritis in the Knee Joint

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

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment.

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan8. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.ope

Exploring the cost-effectiveness of high versus low perioperative fraction of inspired oxygen in the prevention of surgical site infections among abdominal surgery patients in three low- and middle-income countries

Background: This study assessed the potential cost-effectiveness of high (80-100%) vs low (21-35%) fraction of inspired oxygen (FiO2) at preventing surgical site infections (SSIs) after abdominal surgery in Nigeria, India, and South Africa. Methods: Decision-analytic models were constructed using best available evidence sourced from unbundled data of an ongoing pilot trial assessing the effectiveness of high FiO2, published literature, and a cost survey in Nigeria, India, and South Africa. Effectiveness was measured as percentage of SSIs at 30 days after surgery, a healthcare perspective was adopted, and costs were reported in US dollars ($). Results: High FiO2 may be cost-effective (cheaper and effective). In Nigeria, the average cost for high FiO2 was$216 compared with 222 for low FiO2 leading to a -6 (95% confidence interval [CI]: -13 to -1) difference in costs. In India, the average cost for high FiO2 was $184 compared with$195 for low FiO2 leading to a -$11 (95$15 to -$6) difference in costs. In South Africa, the average cost for high FiO2 was$1164 compared with 1257 for low FiO2 leading to a -93 (95% CI: -132 to -65) difference in costs. The high FiO2 arm had few SSIs, 7.33% compared with 8.38% for low FiO2, leading to a -1.05 (95% CI: -1.14 to -0.90) percentage point reduction in SSIs. Conclusion: High FiO2 could be cost-effective at preventing SSIs in the three countries but further data from large clinical trials are required to confirm this