Potential Disease-Modifying Treatment Strategies Targeting Senescence in the Setting of Knee Osteoarthritis
William S Hambright2, Austin Yeargan III1, Justin E Hellwinkel2, Kaitlyn E Whitney2,4, Bailey E Montgomery3, Marc J Philippon4, Thos A Evans4, Bruno Peault5,6, Joseph Buckwalter7 and Johnny Huard2*
1Regenerative Medicine Clinic, Wilmington, USA
2Center for Regenerative Sports Medicine, Steadman Philippon Research Institute, USA
3Center for Genomic Medicine, Massachusetts General Hospital, USA
4The Steadman Clinic, Vail, USA
5MRC Centre for Regenerative Medicine, The University of Edinburgh, UK
6Orthopaedic Hospital Research Center, David Geffen School of Medicine, University of California at Los Angeles, USA
7University of Iowa, Carver College of Medicine, Department of Orthopedics and Rehabilitation, USA
Submission:February 17, 2021; Published: March 17, 2021
*Corresponding author: Johnny Huard, PhD, Chief Scientific Officer, Center for Regenerative Sports Medicine Steadman Philippon Research Institute, 181 West Meadow Drive Suite 1000 Vail, CO 81657, Colorado, USA
How to cite this article: William S H, Austin Yeargan II, Justin E H, Kaitlyn E W, Bailey E M, et al. Potential Disease-Modifying Treatment Strategies Targeting Senescence in the Setting of Knee Osteoarthritis. Ortho & Rheum Open Access J. 2021; 17(5): 555971. DOI: 10.19080/OROAJ.2021.17.555971
Abstract
The prevalence of osteoarthritis (OA) is increasing and projected to affect one in four adults in the United States by 2040. Limitations associated with recreational and vocational pursuits is expected to increase substantially, resulting in a large impact on individuals and the healthcare system. Conservative treatments for knee OA have traditionally focused on ameliorating symptoms through non-invasive and minimally invasive procedures. While conservative treatment modalities are considered the “gold standard” in clinical practice, preventative and restorative therapies are desperately needed to improve quality of life in those suffering from symptomatic OA. A large body of literature exists regarding the mechanisms responsible for the pathogenesis of OA and has enabled the development of alternative treatment modalities, including optimized cell-based therapies (CBTs) and new systemic and intra-articular disease modifying OA drug (DMOAD) approaches. Bone marrow and adipose CBTs offer significant translational advantages in that progenitor cells and bioactive factors can be harvested using minimally invasive technology without the need of in vitro expansion. Enhancing the therapeutic efficacy of these CBTs via senolytic agents also offers a promising new treatment modality. Senolytic agents are considered DMOADs that target senescent cells which release senescenceassociated secretory phenotype (SASP) factors. Attenuating cellular senescence and their secreted constituents via senolytic drugs may offer a novel disease modifying approach for the treatment of OA. In this review, we will briefly summarize OA etiology of the knee, discuss limitations of current treatments of CBTs and DMOADs, and highlight emerging strategies on targeting cellular senescence.
Keywords: Osteoarthritis; Orthobiologics; Cell-based therapies; Mesenchymal stromal cells; Senescence; Senescence-associated secretory phenotype
Abbreviations: OA: Osteoarthritis; CBTs: Cell-Based Therapies; DMOADs: Disease modifying osteoarthritis drugs, MSCs: Mesenchymal Stromal Cells; SASP: Senescence-associated Secretory Phenotype
Introduction
Osteoarthritis (OA) is a progressive degenerative disease of the joint leading to cartilage damage, pain and loss of function [1- 4] affecting an estimated 250 million people worldwide and 27 million people in the United States [5,6]. The knee is the largest synovial joint in the body comprised of synovium, ligaments, avascular cartilage, and different osseous components. Further, the knee joint is a very common site for osteoarthritic pain given the high use and stress subjected to the joint daily [7]. Several important risk factors are associated with OA onset including but not limited to BMI, previous knee injury, age, gender, family history [8]. OA can be generally categorized into two groups: idiopathic (age-associated OA, AAOA) and secondary, which is often after injury or trauma (post-traumatic OA, PTOA) but can also be due to mechanical misalignment. The degeneration of cartilage with OA leads to significant pain and joint dysfunction [2-4]. While causally different, both idiopathic and PTOA share similar symptomology and degenerative drivers that comprise the multi-factorial condition [9].
Currently, there are no effective FDA-approved therapies that are disease modifying interventions to prevent the course of joint destruction due to OA. 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) [10- 12]. Another prominent treatment strategy is the use of intraarticular corticosteroids (CS) to reduce pain and inflammation via targeting production of interleukins, leukotrienes, prostaglandins, and metalloproteinases [13-15]. 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 [16]. This has resulted in the American Academy of Orthopaedic Surgeons (AAOS) being unable to recommend the use of intraarticular CSs [17]. In addition, surgical approaches exist to repair damaged/degenerated cartilage to mitigate the development or progression of OA. These include bone marrow stimulation, osteochondral allograft transplantation, and autologous chondrocyte implantation that have limitations often requiring total joint replacement which itself is not ideal for younger individuals [18-22] [1,4,23-29].
Several alternative strategies to CS are currently available to consumers but are considered experimental. Cell-based therapies (CBTs), disease-modifying osteoarthritis drugs (DMOADs), or a combination thereof, represent appealing alternatives for the treatment of OA [13,30]. More recently, bone marrow and percutaneous adipose tissue CBTs have demonstrated promising short and intermediate term benefits for knee OA [31]. These studies have shown significant improvements in the Visual Analog Scale for Pain, IKDC knee function, Tegner Activity Scale, and Lysholm Knee Scores [32,33]. However, level I evidence of long-term efficacy or significant tissue regeneration is certainly lacking. A critical variable regarding CBT studies has routinely been the discrepancy in the preparation of the orthobiologics product such as the use of point of care devices versus manual preparations in addition to platelet content, platelet activation state, and leukocyte content. One novel and appealing approach for treating age-associated OA (AAOS) and post-traumatic OA (PTOA) 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 [34-37]. Senescent cells are non-proliferative, resistant to apoptosis, and secrete a litany of pro-inflammatory factors that promote disease and systemic aging [38]. While the presence of senescent cells in cartilage has been noticed for decades in patients undergoing total knee replacement, the role in OA pathogenesis remains unclear [39-41]. However, recent evidence points towards a potentially causative role in idiopathic and PTOA including findings that demonstrate significant benefits with senescent cell clearance [36,37]. Thus, senescent cells and their paracrine-acting factors likely play a significant role in OA pathogenesis and has led to several ongoing clinical trials investigating senolytic agents in age-related pathologies, such as frailty (NCT03430037, NCT03675724), Alzheimer’s disease, and knee osteoarthritis (NCT03513016, NCT04129944, NCT04210986). Overall, this review provides an overview of key factors involved in OA progression and currently available CBTs and DMOADs for the treatment of OA. We discuss updates to CBTs in the setting of knee OA with a special emphasis on the contributions of senescence to the disease that offer emerging therapeutic targets.
Paradigms for OA Etiology
Progressive Age-Related Cartilage Degeneration
OA is a multifactorial disease that is affected by mechanical derangements (Figure 1) and other etiological factors [42]. Chondrocytes in the extracellular matrix (ECM) are responsive to cyclic loading by clustering along force vectors relative to the biomechanics of gait [43]. Pathologic static and dynamic loading patterns in the axial and appendicular skeleton initiate remodeling of the ECM in which the articular chondrocytes reside [44-46]. This transformation increases the ratio of type one collagen to proteoglycan in the ECM [44-46]. Proteoglycans in the cartilage matrix break down and lose functional capability with escalation of inflammation [44-46]. The resulting ECM construct stiffens and transfers load directly to the subchondral bone [44-46]. Once the physiologic loading capacity exceeds the physical limits of the subchondral bone, pathologic changes of the osteochondral tissues manifest, compromising the elastic modulus of the subchondral bone [47]. Over time, the concentrated force is directed back into the articular surface of the convex side of the joint, where the same process occurs in a more accelerated fashion. Advanced T2 weighted magnetic resonance imaging (MRI) sequences has allowed a clear delineation of these stages of disease and will likely prove helpful in the future when included as a diagnostic tool and an instrument to objectively measure treatment effects.
Trauma Induced Osteoarthritis
PTOA develops after injury or trauma to the cartilaginous surface caused by impact, shear, and eccentric loading of the joint surface. Sports-related injuries and fractures are the most common mechanisms that predispose to development of PTOA. Furthermore, it is difficult to predict which patients will be predisposed to chronic musculoskeletal issues after trauma. This can be significant for athletes who sustain soft tissue injuries and need to be counseled on their risk for further damage to their joints. Apoptosis and necrosis of chondrocytes secondary to injury is thought to be responsible for degeneration in the acute phase, but perhaps even more significant is the subsequent inflammatory phase which affects cartilage at surrounding sites as well [48]. Catabolic inflammation within the joint induces breakdown of cellular components and offsets mechanical stability of the cartilage, making it further susceptible to degeneration. Although MRI can be a tool to assess cartilage damage, there is currently no modality to predict the rate of degeneration a patient will have in an injured joint.
Altered Signaling Pathways in the Pathogenesis of Osteoarthritis
Repeated cyclic load causes the ECM of articular cartilage and subchondral bone to react through adaptive remodeling and over time becomes mechanically compromised. This is mediated through mechanoreceptors and increased trans-osseous oxygen pressures (PO2) favoring catabolic transformation [49]. As the ECM attempts to remodel, altered joint mechanics continue to disrupt the macromolecular network that often results in the activation of proteinases involved in degenerative and inflammatory pathways. With increasing matrix wear, the chondrocytes embedded within the ECM are exposed to shear force and become subject to autolysis [50]. In addition, fragmented proteoglycans and release of intracellular proteins stimulate infiltrating monocytes to the articular lining to induce an inflammatory response (Figure 2). Although cartilage degrading proteins are offset by anabolic cytokines (i.e., interleukin-1 receptor antagonist [IL-1Ra], interleukin-4 [IL-4], interleukin-10 [IL-10], etc.), tissue inhibitors of metalloproteinases (TIMPs), and TNF-stimulated gene 6 (TSG- 6) HA complexes that limit serine protease activity, [51,52] this balance is shifted towards cartilage degeneration in the setting of OA [53-55].
Patient demographics (i.e., age, sex, comorbidities, body mass index [BMI], etc.) are important factors that often guide clinical decisions; however, clinical signs of OA may be considered subclinical in early phases of the disease due to presence of catabolic (degradative) and inflammatory cytokines and chemokines that contribute to the physiopathology. Although it is not clear how these factors are associated with OA-symptomology, there are several major pro-inflammatory mediators that drive degenerative and inflammatory process, including, but not limited to, matrix metalloproteinases (MMPs) -1, -3, -8, -12 and -13, interleukins (ILs) -1β, -6, and -8, -17, -18, leukemia inhibitory factor (LIF), oncostatin M (OSM), tumor necrosis factor alpha (TNF-α), and prostaglandins [53,56]. In some cases, serial measurements of serum IL-6 and haptoglobin may provide a baseline assessment and guide treatment [56]. Catabolic biomarkers, such as MMPs, have also been shown to upregulate in synovial fluid in early OA and establish a negative feedback loop that causes ECM destruction [55,57-59]. While these studies show promise in the diagnostic and prognostic utility of biomarkers for OA, ascertaining periodic chronicity information and biospecimens longitudinally is a major challenge [60]. Given these challenges, there remains a paucity of longitudinal studies that have a common focus on individual biomarkers that may predict incidence or progression of two common OA etiologies (PTOA and age-related OA) [61,62]. In response, several working groups have been established over the last decade to set a framework for the evaluation of joint proteome changes and their impact on the progression of the disease using standardized endpoints [60,62-65]. Continued observations from these working groups are warranted to validate the clinical utility of biomarkers for diagnostic purposes, as well as prognostic purposes following CBT or DMOAD interventions [56,62,64].
Emerging Treatment Strategies for Osteoarthritis
Cell-based Therapies
Cell-based therapies (CBTs) can be considered an anabolic (tissue repairing) treatment utilizing a two-component design; a viable nucleated cell component and a soluble protein component (Figure 3). Progenitor cells, namely mesenchymal stem (stromal) cells (MSCs), hematopoietic stem cells (HSCs), and myeloid precursors [66], have been used as a treatment modality to attenuate OA-symptoms. Specifically, MSCs are capable of self-replication and specialization into many tissue types, including cartilage, bone, tendon, muscle, and fat [67]. MSCs direct tissue responses to injury, stimulate resident stem cells, and prompt apoptosis and cell lysis to initiate a healing response in musculoskeletal tissues. The degree of local inflammation determines whether MSCs respond with a pro- or anti-inflammatory phenotype, which is important when considering their clinical use [68]. Despite their capacity to form clonal cell lines and specialize into tissues of mesodermal lineage, the immunomodulatory and antiinflammatory effects are the most responsible for the clinical experience of pain relief [69], and potentially the most important mechanisms to be studied. A common source of MSCs is from the bone, most often sourced from the iliac crest [70]. However, MSCs makeup only approximately 0.001% of the bone marrow cell population and have presented hurdles in the clinic including donor site morbidity and pain [71]. In addition, there seems to be variability between content depending on the type of tissue the cells are extracted from and the demographics of the donor [72]. Indeed, more clinical studies are needed to characterize cellular profiles (including MSC surface antigens) to better understand the association between these profiles and clinical outcomes.
Due to the limitations of bone marrow CBTs, other cell populations, namely adipose derived stem cells (ADSCs), have garnered interest as of late [73]. These cells, collected from the stromal vascular fraction of adipose tissue lipoaspirate offer a practical advantage in that they are more accessible and provides CD73, CD90, CD105, CD106 positive multi-potent progenitor cells capable of chondrogenic differentiation [74]. Further, ADSCs have demonstrated pro-regenerative immunomodulatory behavior, including the promotion of inhibitory macrophages and T regulatory cells which may offer additional means to improve clinical symptoms coupled to cartilage regeneration [75]. Indeed, several clinics routinely isolate SVF from lipoaspirate through minimal manipulation practices for various orthopedic indications, including OA. Of note, current evidence suggests that CBTs are limited in efficacy when not considering alterations in joint mechanics. In this setting, it may be most appropriate to perform CBT in early onset OA patients or non-surgical candidates; however, a defined criterion is needed to provide clinical guidance for this subset of patients that are often asymptomatic.
Targeting Cellular Senescence
Although OA is thought to be a disease characterized by gradual deterioration of articular cartilage leading to mechanical failure, emerging evidence highlights the importance of cellular dysregulation. Chondrocytes and other joint cells in both AAOA and PTOA are characterized by genomic instability, telomere shortening, dysregulated nutrient sensing, upregulated proinflammatory signaling, mitochondrial dysfunction, and loss of proteostasis [76-78]. Importantly, all these features are hallmarks of cellular senescence and its associated phenotypes, and indeed, senescent chondrocytes, synoviocytes, synovial macrophages have all been found to be present in OA patients [76-78]. Senescence is a cell state defined by loss of proliferative capacity, increased metabolic activity, and importantly, resistance to apoptosis. Senescent cells promote disease and tissue dysfunction via the release of cartilage degrading enzymes and pro-inflammatory mediators otherwise known as the senescence-associated secretory phenotype (SASP) [38]. Cellular senescence can be induced by a variety of extrinsic (mechanical stress, damage signals, inflammatory factors) and intrinsic signals (reactive oxygen species, DNA damage, mitochondrial dysfunction) that leads to the production of a SASP, a collection of various proinflammatory cytokines/chemokines, proteases (MMPs and ADAMTS-4 and -5), and other factors that initiate senescence in neighboring cells and promote disease and tissue dysfunction [38,79].
The role of senescent cells in the pathogenesis of OA has garnered significant interest recently [35]. In support of a causative role for senescent cells in OA, it was demonstrated that injection of senescent cells into the joint capsule of healthy mice was found to induce radiographic and histological evidence of OAlike conditions including severe cartilage degeneration, erosion of femoral condyles, subchondral bone structure alteration, osteophyte formation, and meniscal damage [80]. Inversely, other groups have shown that local clearance of senescent cells within the joint capsule significantly reduces development of injury-induced OA and promoted a pro-regenerative environment [37]. The use of transgenic mouse models also strongly implicates cellular senescence in driving OA. Using the p16-3MR mouse model, which allows for the visualization of high p16INK4a expressing cells in live animals, it was found that senescent chondrocytes increased dramatically following ACLR-induced OA [37]. This was associated with marked increases in SASP factors, such as MMP-13, IL-6, and IL-1β, all of which are known to be largely present in OA [36,79]. In INK-ATTAC mice, a slightly different transgenic model that harbors drug inducible senescent cell elimination via caspasedependent apoptosis, it was found that removal of senescent cells late in life could prevent or delay age-related cartilage loss and retain structural integrity of the cartilage like that in young mice [81]. The findings using the p16-3MR and INK-ATTAC models further suggest a role for senescent cells in not only AAOA, but PTOA as well. Senescent cells and their SASP are an important source of pro-inflammatory mediators and pain, which is the most bothersome manifestation of OA for patients. The SASP produced by senescent cells includes cytokines that elicit inflammation (IL- 6, TNF-α, IL-1β) but also chemokines (IL-8, CCL5, CCL19) that attract and activate synovial immune cells [36,79]. Following trauma, infiltrating immune cells play an important role in tissue repair through tissue remodeling and debris clearing, which is temporally coordinated via cytokine/chemokine bursts. Thus, SASP factors work in concert with the localized immune response to potentiate or exacerbate repair, fibrosis, or chronic diseases pathogenesis. This is further confounded by the fact that senescent cells likely play a role in normal tissue healing as they accumulate rapidly following injury, attract immune cells necessary for repair, and are subsequently removed by immune cells, namely natural killer cells [79,82]. However, with age, senescent cells accumulate and disrupt this balance. The exact SASP factors most responsible for pain in PTOA or AAOA have yet to be fully elucidated, but several pro-inflammatory SASP factors have been linked to pain including IL-1, IL-6, TNF-α, and PGE2/COX-2 [36]. PGE2/COX-2 is especially compelling as a mediator of inflammatory pain given PGE2 is known to bind to E prostanoid receptors (EP1-4) which are present in sensory neurons of the peripheral nervous system. Indeed, it has been found that both PGE2 and COX-2 were elevated in the synovium, bone, and meniscus of human OA explants [83]. It has also been recently demonstrated in preliminary studies that oral dosing of senolytic drugs can preserve cartilage proteoglycan content in a progeroid mouse model that exhibits spontaneous OA symptomology, the Zmpste24-/- model (unpublished data). Clinically speaking, recent clinical trials have highlighted a potential causal role for cellular senescence in AAOA and PTOA and senescent cells have been found in nearly all tissues of the arthritic joint in preclinical models and in tissues isolated from arthroscopy procedures [39,40,77-79]. Senescent chondrocytes have also been found to be enriched near osteoarthritic lesions, strongly suggesting a disease promoting effect on neighboring cells (40). Thus, senescent cells and their associate SASP profiles likely play a role in both the clinical manifestation of OA (pain) and disease pathogenesis (tissue dysfunction and cartilage degradation).
Discussion
Over the last decade, patient reported results following CBT intervention for the attenuation of OA-symptoms have been increasingly successful. While a great deal of additional research is needed, so far results have been encouraging and many patients have been able to delay or avoid joint replacement surgery and its inherent risks altogether. Although an ideal solution for knee arthritis has yet to present itself, CBTs and DMOADs provide another tool to combat OA symptoms and potentially treat the underlying disease. However, some reservations should be had. Despite the wide use of CBTs in the field of orthopedics, there are little data on the cost to benefit ratio of biologic treatments due to inconsistencies between providers. In 2009, it was estimated that more than 570 clinics in the U.S. marketed stem-cell therapies for the treatment of various musculoskeletal conditions [84]. The term “stem cell treatment” is an oversimplified label often used to designate treatment with concentrated nucleated marrow cells and selected proteins, including synovial mesenchymal stromal cells, muscle-derived stem cells (MDSCs), adipose-derived stem cells (ADSCs), bone marrow stem cells (BMSCs), peripheral blood stem cells (pericytes). The clinical efficacy of CBTs certainly warrants further study and may call for an education campaign from the AAOS and ABOS to minimize potential patient exploitation [17,36,79]. The responsiveness and variability in reported success rates between patients likely reflects our limited understanding of disease pathogenesis and subsequent therapeutic interaction and not the limited efficacy of the CBTs themselves. There are no accepted ‘best practices’ for regenerative techniques in orthopaedic surgery or published criteria for CBT treatment.
Targeting senescence may offer a novel therapeutic target for the treatment of AAOA and PTOA. In fact, several senolytic compounds that selectively target and inhibit anti-apoptotic pathways in senescent cells have been recently identified and shown to kill senescent cells in vitro and in vivo without affecting quiescent or proliferating cells [35]. Senolytics are a potentially innovative DMOA drug class that is quite appealing given they target senescent cells directly, thereby inducing cell death and abrogating systemic SASP factors [35], with minimal to zero off target effects. There are indeed a few reports demonstrating the efficacy of senolytic drugs in reducing disease phenotypes in PTOA [36,37,85]. 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 [35,86,87]. Further, many senolytic compounds target several different antiapoptotic pathways, allowing for a multi-hit approach [35,86,87] and only intermittent administration is likely necessary as only brief disruption of anti-apoptotic pathways is sufficient to kill senescent cells [87]. Cell division dependent resistance is not a concern either for senolytics as senescent cells do not divide and therefore cannot acquire selectively advantageous mutations such as those found in treating cancers or infectious agents. Finally, another benefit to using senolytic drugs is they can be readily incorporated into established clinical practice via intra-articular delivery and are effective via oral administration as well [37].
OA is a debilitating and costly joint disease that affects millions of individuals each year for which there are currently no available disease modifying therapies [17,36,79]. Identifying new orthobiologic strategies that modulate causal elements of pathology including CBTs from various tissue sources may transform standard of care. While promising, more scientific evidence derived from randomized controlled clinical trials is necessary prior to promotion and widespread use of these therapies. However, DMOADs including senolytic agents may compliment CBTs in combination or as front-line treatment options during prodromal stages of disease (i.e., advanced age). Senolytic drugs may offer a promising new approach for the treatment of not only OA symptoms, but a fundamental driver of pathogenesis, senescent cells and their SASP.
Conclusion
Osteoarthritis (OA) is an incurable debilitating disease that is the most common joint disease affecting over 10% of the population aged 60 and older [88]. Few treatment options exist, and most therapies involve analgesics that target symptoms of OA, such as pain and swelling. Thus, preventative, and restorative therapies are desperately needed to improve quality of life. Cellbased therapies such as concentrated bone marrow aspirate take advantage of autologous mesenchymal stromal cells (MSCs) and offer a uniquely promising disease modifying treatment modality to reduce catabolic processes degenerating articular cartilage and subchondral bone deterioration, reduce pain, and/or restore motion and function. However, the quantity and relative makeup of the pro-regenerative factors and cells within bone marrow aspirate concentrate that drive positive clinical outcomes is currently unknown with significant variance in clinical efficacy. Resident senescent cells and their tissue degrading SASP factors are prominent in various joint tissues and likely promote agerelated and trauma induced OA. Pharmacologically targeting senescence and the SASP via senolytic agents thus offers a novel therapeutic approach for OA. Indeed, targeted elimination of senescence cells in preclinical studies has been shown to reduce OA symptomology [89] while the injection of senescent cells into knee joints of mice exacerbates OA symptomology [80]. Current randomized controlled clinical studies are also underway by our group and others to investigate the efficacy of senotherapeutic agents through oral administration (NCT03513016, NCT04129944, NCT04210986). These studies include patient reported measurements of pain and function (IKDC, Lysholm, TEGNER, WOMAC), radiographic grading (Kellgren Lawrence), MRI assessment of cartilage health (T2 mapping), biomarker assessment of peripheral blood and bone marrow aspirate concentrate. Other outcome measures include the evaluation of senescence indices such as serum and bone marrow SASP markers, senescence quantification in peripheral blood mononuclear cells (PBMCs), and senescence related transcript levels of PBMCs. Other delivery modalities are also an option for senolytic therapy including intra-articular injection and potentially to even to treat orthobiologic products directly either intraoperatively or during processing prior to autologous administration. Most importantly, because senescent cell accumulation and chronic sterile inflammation are fundamental properties of aging, senotherapies may act as Disease-modifying OA drugs (DMOADs) in the context of idiopathic and trauma induced OA.
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