ICRS 2019 - Conference Calendar
8.2.1 - Antibodies & Cytokines
IntroductionThe multifaceted nature of osteoarthritis (OA) places high demands on potential therapeutics, which ideally should be capable of eliciting multifactorial responses to effectively treat this complex disease. Current clinical therapies only address the pain of OA disease and are not yet able to perform disease modifying activity and rebuild tissue in the joint. Fundamentally, the causes of OA development remain unknown. This talk will cover a potential underlying disease mechanism, “cellular senescence” and develop therapeutics to specifically target these cells in OA disease
ContentSenescent cells (SnCs) are a newly implicated factor in the development of OA that occur in associate with aging and trauma. “Cellular senescence” is characterized by a proliferation arrest, which protects against cancer, as well as other changes that can also contribute to aging phenotypes and pathologies1. SnCs accumulate with age in many vertebrate tissues, including articular cartilage, where they promote pathological age-related deterioration. These and other tissue pathologies are presumably mediated by the secretion of extracellular proteases, proinflammatory cytokines, chemokines, and growth factors, termed the “senescence-associated secretory phenotype” (“SASP”), by SnCs. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells’ relevance to disease was unclear. These cells, along with their inflammatory cytokine secretions, are responsible for OA development2, 3. Thus, this presentation will focus on the causative role of SnCs in the development of posttraumatic and age-related arthritis along with a potential senolytic therapies that selectively remove SnCs as a new treatment for OA. The second part of this presentation will focus on SnCs-associated extracellular vesicles (EVs) and their contents such as microRNAs and proteins as a diagnostic for arthritic disease and indicator for therapeutic efficacy of senolytic treatment4.
References1. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005 Feb.120(4):513–522.
2. Jeon OH, Kim C, Laberge R-M, Demaria M, Rathod S, Vasserot A, Chung JW, Kim DH, Poon Y, David N, Baker DJ, Deursen JM, Campisi J, and Elisseeff JH. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature Medicine. 2017 April. 23(6):775-781.
3. Jeon OH, David N, Campisi J, and Elisseeff JH. Senescent cells and osteoarthritis: a painful connection. JCI. 2018 April. 128(4):1229-1237.
4. Jeon OH, Wilson DR, Clement CC, Rathod S, Cherry C, Powell B, Lee Z, Khalil AM, Campisi J, Santambrogio L, Green JJ, Witwer KW, Elisseeff J. H. Senescence-associated extracellular vesicle serve as osteoarthritis disease and therapeutic markers. JCI Insight. 2019 April. 4(7):e125019.
AcknowledgmentsThe authors acknowledge financial support from a fellowship from the Glenn Foundation for Medical Research (to O.H. Jeon).
8.2.2 - PRP, BMC, SVF
Osteoarthritis (OA) is the most common form of arthropathy, with a prevalence of approximately 10% in the population aged over 60 years, representing one of the major causes of pain, disability, and health economic costs worldwide . OA can be initiated by different mechanisms and conditions but, independently form its aetiology, ultimately results in a common end point. If not properly treated, it can evolve towards symptomatic and advanced stages which may require sacrificing procedures. Unfortunately, current conservative treatments for OA are not very effective, explaining the increasing demand for prosthetic replacement. Indeed, nonsurgical treatments such as physiotherapy, anti-inflammatory, and anti-pain medications all have modest and short-lasting efficacy. In particular, early OA onset poses special therapeutic challenges for active patients; thus, the reward for any prevention strategy or delay of the disease is very relevant. In this context, biological injective approaches (such as PRP, BMC, SVF) have recently gained increasing attention due to their anti-inflammatory and immunomodulatory properties, tolerability, and regenerative potential .
Intraarticular injections of these biological products for the treatment of early OA can offer great advantages by allowing bioactive molecules and/or cells within the joint space to target the injured tissues through the interaction with recipient cells, possibly leading to better outcomes without significant risks due to the minimally invasive nature of the injective approach.
Growth factors (GFs) play a significant role in musculoskeletal tissues homeostasis and repair, and GFs showed the ability to stimulate cartilage matrix synthesis and pro-anabolic responses in chondrocytes. The limited success of pre-clinical and clinical trials with various GFs, and the recent developments in blood derivatives led to a potential paradigm shift in GF therapy for OA treatment. In fact, it might be more reasonable to consider a cocktail of GFs rather than a single GF treatment, and blood derivatives have been proposed as safe, easy, cost-effective, and minimally invasive strategy to influence the joint environment favouring the restoration of a homeostatic balance and possibly the regeneration of degenerating tissues. In particular, among blood-derived products PRP is gaining more and more attention due to the GFs and anti-inflammatory molecules stored in platelet α-granules. Beside an extensive preclinical literature supporting PRP, only a few high-level studies have been currently published. Nonetheless, existing RCTs provide the evidence of superiority in comparison to placebo, and overall they show the benefit of PRP injections for knee OA treatment with superior effects to what reported for viscosupplementation . Importantly, outcomes depend on age and the level of cartilage degeneration with better results in younger patients with early OA, although the duration of the beneficial effect, roughly 6–12 months, does not support a regenerative effect on articular cartilage, but rather suggests only a temporary homeostatic improvement of the joint environment, especially in less advanced cases . Lately, the potential of PRP and the superiority with respect to HA injections have been questioned by a double-blind RCT on a large cohort of patients, which documented a similar response to treatments at 12 months and only a slight and questionable superiority of PRP up to 5 years .
Mesenchymal stem cells (MSCs) are considered another promising option for OA treatment. MSCs are multipotent progenitor cells with capability of self-renewal, high plasticity, immunosuppressive and anti-inflammatory action, and the possibility to differentiate into selected lineages. Moreover, these cells, derived from perivascular cells called "pericytes", play a key role in the response to tissue injury not only by differentiating themselves but also by inducing repair/regeneration processes at the site of damage through the secretion of several bioactive molecules . Despite extensive preclinical research and promising findings reported in the clinical practice , both their potential and limitations for the use in patients remain controversial . The use of many cells through expansion has been questioned by studies showing similar or even better results through the use of concentrates which may offer a lower number of cells but on the other hand the benefit of administering MSCs in their niche and therefore allowing them to act in more favourable conditions . Mesenchymal and haematopoietic stem cells form a unique bone marrow niche and their co-presence could lead to the best results . Similarly, the progenitor cell-rich product obtained intraoperatively from adipose tissue, named SVF, contains preadipocytes, vascular endothelial cells, and pericytes (ASCs). Also in this case, the maintenance of the stromal cell niche architecture could provide an advantage . Based on these observations, MSC-rich concentrates from bone marrow and adipose tissues have been applied, suggesting promising clinical results in the treatment of OA.
However, despite the promising findings in both in vitro and pre-clinical biological studies, there is still a lack of clear clinical evidence to support the clinical efficacy of PRP, BMC, and SFV in OA. In fact, this research area is still in its infancy, and more robust studies are needed to confirm and optimize their efficacy by identifying the most suitable preparation procedure, the best application modality, and the most responsive patients and disease phases.
1. Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, Carr AJ. Osteoarthritis. Lancet. 2015 Jul 25;386(9991):376-87.
2. de Girolamo L, Kon E, Filardo G, Marmotti AG, Soler F, Peretti GM, Vannini F, Madry H, Chubinskaya S. Regenerative approaches for the treatment of early OA. Knee Surg Sports Traumatol Arthrosc. 2016 Jun;24(6):1826-35.
3. Filardo G, Kon E, Roffi A, Di Matteo B, Merli ML, Marcacci M. Platelet-rich plasma: why intra-articular? A systematic review of preclinical studies and clinical evidence on PRP for joint degeneration. Knee Surg Sports Traumatol Arthrosc. 2015 Sep;23(9):2459-74.
4. Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A, Kon E, Filardo G. Platelet-Rich Plasma Versus Hyaluronic Acid Injections for the Treatment of Knee Osteoarthritis: Results at 5 Years of a Double-Blind, Randomized Controlled Trial. Am J Sports Med. 2019 Feb;47(2):347-354.
5. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011 Jul 8;9(1):11-5.
6. Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013 Aug;21(8):1717-29.
7. Perdisa F, Gostyńska N, Roffi A, Filardo G, Marcacci M, Kon E. Adipose-Derived Mesenchymal Stem Cells for the Treatment of Articular Cartilage: A Systematic Review on Preclinical and Clinical Evidence. Stem Cells Int. 2015;2015:597652.
8. Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med. 2014 Aug;20(8):833-46.
A. Boffa, C. Cavallo, G. Merli
8.2.3 - Extracellular Vesicles from Mesenchymal Stem Cells: Results & Perpectives Towards an Acellular Therapy in Rheumatic Diseases
Among osteo-articular diseases, osteoarthritis (OA) is the most common arthropathy whose incidence increases with population ageing, obesity, genetic factors or following traumas. Rheumatoid arthritis (RA) is the second leading cause of disability.
Although both diseases result in articular cartilage degradation, RA is a highly inflammatory disease characterized by the presence of an invading inflammatory pannus in joints while OA is characterized by low grade chronic inflammation together with sub-chondral bone alterations. Current treatments are either symptomatic to relieve pain or anti-inflammatory using immunosuppressive drugs including biotherapies in case of RA. However, no curative therapeutic options can be provided to patients. In this context, the therapeutic effect of mesenchymal stem cells, also known as mesenchymal progenitor or stromal cells (MSC), has been investigated. MSC display regenerative and repair activities through the secretion of many trophic paracrine factors that can influence joint repair (1). Recent data suggest that most of the secreted factors released by MSC are conveyed within extracellular vesicles (EV) that reproduce the main function of the parental cells. Indeed, the use of EV instead of MSC might be an attractive alternative for rheumatic diseases. We will present in vitro and non-clinical data using MSC-derived EV in the murine models of inflammatory arthritis and of OA (2-3). Perspectives for the use of MSC-EV in rheumatology will be discussed.
Cosenza S, Ruiz M, Maumus M, Jorgensen C, Noël D. Pathogenic or therapeutic extracellular vesicles in rheumatic diseases: role of mesenchymal stem cell-derived vesicles. Int J Mol Sci, 2017: 18:889-904
Cosenza S, Ruiz M, Toupet K, Jorgensen C, Noël D. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Scientific reports, 2017, 7:16214
Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O, Jorgensen C, Noël D. Mesenchymal stem cells derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics 2018, 8:1399-1410