Osteoarthritis is a progressive degenerative disease of the joint leading to cartilage
damage, pain and loss of function affecting an estimated 250 million people worldwide and 27
million people in the United States . Currently, there are no effective FDA-approved
therapies that are disease modifying interventions to prevent the course of joint destruction
due to Osteoarthritis The most prevalent first-line treatment for OA is to mitigate pain and
restore function with a combination of weight management, physical therapy, mind-body
exercises, and analgesia with paracetamol or NSAIDs (topical or oral) . Another prominent
treatment strategy is the use of intra-articular corticosteroids (CS) to reduce pain and
inflammation via targeting production of interleukins, leukotrienes and prostaglandins
However, the palliative effects of CS for OA are often short-term, can potentially lead to
chondral fissuring and promotion of dose-independent structural changes in cartilage, and
there are no consistent reports of efficacy .
One novel potential and appealing approach for treating Osteoarthritis is through the local
and systemic elimination of senescent cells. Senescent cell burden increases significantly
with age and has been shown to promote several age-related pathologies including degenerative
joint conditions.
Senescent cells are non-proliferative, resistant to apoptosis, and secrete pro-inflammatory
factors that promote disease and systemic aging . Cellular senescence can be induced by a
variety of extrinsic and intrinsic signals that leads to the production of a collection of
various proinflammatorycytokine and other factors that initiate senescence in neighboring
cells and promote disease and tissue dysfunction.
Thus, senescent cells and their associate senescence associated secretory phenotype profiles
likely play a role in both the clinical manifestation of OA (pain) and disease pathogenesis
(tissue dysfunction and cartilage degradation. The overall safety and efficacy of several
senolytic drugs to treat chronic diseases have been demonstrated in several preclinical
studies and more recently in phase I-II clinical trials for OA. For example, the senolytic
drug Dasatinib is an FDA approved drug for leukemia with few side effects while other
senolytic drugs like quercetin and fisetin are naturally occurring plant flavonoids tolerable
at relatively high doses . Clinical trials about the use of senolytic agents as therapeutic
agents in different clinical cases:-
- Senescent Cell Burden in Hematopoietic Stem Cell Transplant Survivors (Mayo Clinic,
NCT02652052 )
- Senolytic Therapy to Modulate Progression of Alzheimer's Disease ( The University of
Texas Health Science Center at San Antonio
,NCT04063124)
- Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease:
Effect of Senolytic Agents (Mayo Clinic NCT02848131)
- COVID-FISETIN: Pilot in SARS-CoV-2 of Fisetin to Alleviate Dysfunction and Inflammation
(Mayo Clinic NCT04476953)
- Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults (
Mayo Clinic NCT03675724)
- Inflammation and Stem Cells in Diabetic and Chronic Kidney Disease ( Mayo Clinic
NCT03325322 ) NLRP3 Inflammasome:- Inflammasomes play a crucial role in innate immunity
by serving as signaling platforms which deal with a plethora of pathogenic products and
cellular products associated with stress and damage. By far, the best studied and most
characterized inflammasome is NLRP3 inflammasome, which consists of NLRP3
(nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing
receptor 3) The hyperactivation of NLRP3 inflammasome is involved in a wide range of
inflammatory diseases. The search and development of anti- inflammatory drugs from
natural sources of plants has received extensive attention.licorice extract has high
activity and wide therapeutic effects.it has reported that glycyrrhizin could ameliorate
fibrosis and inflammation via inhibiting NLRP3 inflammasome activation and NF-κB
signaling pathway. Aim of work:- To determine the efficacy of Natural senolytic agents
and NLRP3 Inflammasome inhibitors for reducing knee symptoms and effusion- synovitis in
patients wih symptomatic knee Osteoarthritis and knee effusion /synovitis.