Osteoarthritis (OA) remains to constitute a large burden to healthcare and negatively impact the quality of life; along with other conditions ranked as 11th highest contributors of global disability. The estimated prevalence of problematic hip/knee OA is approximately 242 million globally; 3.8% accounting for decreased quality of life (QoL) and societal burden. Knee OA (KOA) carries a higher incidence when compared to other joints (i.e., hip), increasing to 60% among the obese population. Of note, a population-based cohort study published in 2008 estimated a 45% lifetime risk of symptomatic knee osteoarthritis. Specifically, KOA was shown to be affecting nine million adults (over the age of 45 years) in the United States with symptoms ranging from moderate to severe. With the escalation of an aging population, sedentary lifestyle, and obesity, the number of patients affected with KOA is undoubtedly on the rise.
The concept of age-related joint degeneration in the event of KOA has been substituted by other theories and factors. In fact, KOA has been shown to be the end result of a chronic interplay between heterogeneous systemic and local reactions. Systemic factors include age, race, ethnicity, and diet, while local ones include body-mass-index (BMI), trauma history, occupational, and mechanical factors. The aforementioned factors, along with indigenous biologic factors (i.e., cytokine homeostasis) result in trivial changes at the knee joint, particularly at the area interspacing between the subchondral bone and the articular cartilage, which becomes evident over time. Owing to this effect, an increase in bone mass and trabecular thickness ensues with reduced ability to withstand stress and compression impact on cartilage; the stage at which chondrocyte cell senescence occurs. Exhibited degeneration of the articular cartilage is a pathognomic feature for OA associated with bone remodeling, osteophyte formation, capsular distribution, and periarticular muscle atrophy. The complexity of cartilage is derived from multiple building blocks and constituents such as chondrocytes type II, collagen, proteoglycan, and an abundantly hydrophilic extracellular matrix containing highly complex meshwork of cytokines and growth factors secreted by surrounding synovial cells and chondrocytes. Prolonged exposure to stressors including reactive oxygen species (ROS) and nitric oxide (NO) in turn trigger macrophages and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kβ). They play an important role in immune regulation and activation of cytokines which are associated with inflammation and ultimately cause disruption of homeostasis in the synovial fluid. Other important associated inflammatory molecules include IL-1 β, TNF-α, INF- γ, TGFβ, MMP-9, and MMP-13, all of which contribute to pathologic hallmarks in the pathogenesis of OA.
Current conventional therapy of OA is mainly focused on providing symptomatic control over hindering disease course progression. Commonly used radiographic grading systems for KOA include Kellgren-Lawrence (K/L). Along with exercise therapy, physical therapy, and weight reduction to strengthen adjacent muscles, current pharmacologic treatment includes acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), gabapentin, pregabalin, and opioids, which are used for K/L grade 0-1. Other means include valgus directing force bracing. Intra-articular (IA) corticosteroid injections are commonly prescribed as a symptomatic treatment for grade ≥ 2 upon which osteophyte formation, joint space narrowing, subchondral sclerosis, and deformity of the joint are evident. Subsequently, total knee arthroplasty (TKA) becomes an option for K/L grade 3-4. It is an invasive procedure associated with a significant number of complications. It was shown that 20% of patients who underwent TKA will have persistent knee pain with a possible need for TKA revision and is subject to further risk and morbidity including loss of function within a year after the procedure. Moreover, with the uncertainty of progression and symptomatic treatment following TKA, it was estimated that 61% of medical expenses are spent on TKA procedures.
Compared to conventional therapy which provides symptomatic treatment, multiple randomized control trials (RCTs) have demonstrated promising potential for stem cell therapies tackling OA morbidity and healthcare burden. The concept of stem cells arises from multipotent cells which have the ability to differentiate into different cell types and possess auto-regeneration according to the body’s needs. These cells can be readily extracted from tissues in the body including the bone marrow, adipose tissue, and the synovium. Of note, MSCs are adult stem cells (ASCs) derived from the mesodermal origin and have the ability to differentiate into different connective tissue cells including osteocytes, adipocytes, and chondrocytes. In vitro, MSCs were shown to have the ability to differentiate into chondrocytes and enhance the proliferation of resident progenitor cells in vivo. With the help of growth factors and extracellular matrix proteins, MSCs demonstrated the ability to create a repair microenvironment that could explain the postulated theory of associated pain reduction and the termination of the disease progression cycle. Subsequently, this method of autologous repairing gives rise to the activation of senescent, metabolically active chondrocytes’ ability to repair damaged tissue. Trials suggested that transplanted MSCs in the joint are activated and subsequently express anabolic genes such as the Indian hedgehog and other ‘hit and run’ genes that enhance collagen type synthesis, analgesic peptide transcription, and the production of various anti-inflammatory cytokines and analgesic proteins. The aforementioned disease-modifying properties build an evidence-based tool for MSC therapy in the context of OA disease progression and stabilization.
Performed clinical trials have subjectively depended on different scoring systems in assessing the effect of engrafted MSCs including the Knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario, and McMaster Universities Arthritis Index (WOMAC), and the Visual Analog Scale (VAS). According to Buzaboon et al., MSCs treatments demonstrated pain reduction and improved knee joint function post-intervention from baseline according to different parameters such as KOOS, VAS, and WOMAC. Most trials have demonstrated a peak in positive effects occurring between the sixth and 12th months following treatment. However, subjectively assessed results were not statistically significant in most trials selected in the study. This was assumed to be due to the late intervention with MSCs to treat OA, which was probably at an advanced stage. The theory is that MSC implantation is more effective in OA when provided at the early stages of the disease. Nonetheless, MSCs implantation in OA has been shown to be a superior approach to conventional therapy. This can be explained by the fact that MSCs treatment can hinder inflammation, restore vital tissue components and damaged cartilage, and the negligible number of serious local or generalized systemic adverse events and complications. However, with the early promising results of MSCs therapy in OA, many questions regarding precise mechanisms remain unexplored. There is still a need for further clinical trials and studies to be performed at the early stages of OA (K/L Grade 0-2), examining different cell culture preparation, and exploring different dosing intervals, frequency of therapy, and appropriate delivery method.
Precision Pain Care and Rehabilitation has two convenient locations in Richmond Hill – Queens and New Hyde Park – Long Island. Call the Richmond Hill office at (718) 215-1888, or (516) 419-4480 for the Long Island office, to arrange an appointment with our Interventional Pain Management Specialist, Dr. Jeffrey Chacko.
