Using cellular therapies for canine joint treatment part 1

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1 Vet Times The website for the veterinary profession Using cellular therapies for canine joint treatment part 1 Author : Karen Perry Categories : Companion animal, Vets Date : April 25, 2016 ABSTRACT Osteoarthritis (OA) is a common problem in dogs and management can be challenging. NSAIDs are an integral part of OA management, but concerns exist regarding side effects. Despite multimodal management with NSAIDs, additional analgesics, nutraceuticals, exercise modification, physical therapy and weight management, some dogs do not achieve a pain-free state and a large unmet need exists for further options against OA-related discomfort. Additions to the armoury include mesenchymal stem cells and autologous platelet therapy. While further research is required for these treatments to elucidate the exact mechanism of action and duration of effect, current evidence supports their use in patients that have failed to respond adequately to more conventional therapies. Osteoarthritis (OA) is a common progressive joint ailment affecting 20% of dogs more than one year of age (Innes et al, 2010; Roush et al, 2010; Figure 1). Figure 1. Ventrodorsal and lateral radiographs of the pelvis of a 10-year-old Old English sheepdog 1 / 11

2 with severe coxofemoral osteoarthritis secondary to hip dysplasia. The associated inflammation and cartilage damage can lead to considerable pain and disability (Rausch-Derra et al, 2015). Treatment is typically intended to slow disease progression and ameliorate clinical signs, and involves interventions such as control of bodyweight, provision of appropriate nutrition, exercise, physical therapy and administration of drugs to control pain and inflammation (Roush et al, 2010). While studies support these various treatment options (Beraud et al, 2010; KuKanich et al, 2012; Vandeweerd et al, 2012) none exist, short of joint replacement surgery, to offer a cure (Figure 2). Many dogs continue to suffer with chronic pain associated with OA, even with multimodal management protocols, and effective treatments are certainly required. Parsons and Murrell (2015a, 2015b and 2016) wrote a comprehensive review of OA diagnosis and management. As a follow-up, this article will cover some of the novel treatment modalities available, as well as promising options for the future. While advances are being made in pursuit of targeted pharmacologic approaches (to be discussed in part two), research is also progressing in the field of cellular therapy as an option for dogs with OA-related pain that proves refractory to other treatments. In OA, the overproduction of destructive and proinflammatory mediators balances in favour of catabolism rather than anabolism, which, in turn, leads to the progressive destruction of articular cartilage (Mortellaro, 2003; Figure 3). In contrast to drug therapy, cellular therapies do not rely on a single target receptor or pathway for their action, but function trophically through cytokines and growth factors (Caplan and Dennis, 2006) to encourage regeneration or restoration of a more optimal joint environment. Advanced therapies Figure 2. A Labrador with severe osteoarthritis of both elbows secondary to medial coronoid process disease, more severe on the right. It was treated initially with arthroscopic debridement at 18 months of age (A), but at four years of age, osteoarthritis had progressed and was nonresponsive to multimodal medical management necessitating total elbow replacement on the right. Radiographs show preoperative craniocaudal (B) and mediolateral (C) views and immediate 2 / 11

3 postoperative craniocaudal (D) and mediolateral (E) views. Advanced therapies refer to some treatments focused on regenerative medicine aiming to promote regenerative or reparative phenomena on the degenerative joint. Among these therapies are autologous platelet therapy and mesenchymal stem cells. Autologous platelet therapy Intra-articular injection of autologous platelets holds promise as a treatment for OA in dogs. Growth factors present in platelets reportedly can enhance the regenerative processes in OA joints (Textor, 2011). Elaboration of growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF) vascular endothelial growth factor (VEGF), transforming growth factor? (TGF?), basic fibroblast growth factor (bfgf) and platelet factor-4 from the? granules of platelets can directly promote healing (Fortier et al, 2011; Nguyen et al, 2011), and growth factors may recruit stem cells to the site of application facilitating tissue repair (Schmidt et al, 2006; Kajikawa et al, 2008; van den Dolder et al, 2006). These growth factors have specific activities on cartilage regeneration and an antiapoptotic effect on chondroblasts: PDGF regulates secretion and collagen synthesis EGF stimulates cell proliferation, endothelial cell chemotaxis and angiogenesis VEGF increases vascular permeability and angiogenesis TGF? stimulates the proliferation of undifferentiated mesenchymal cells and stimulates endothelial cell chemotaxis and angiogenesis bfgf promotes the growth and differentiation of chondrocytes and osteoblasts, and stimulates mitogenesis of mesenchymal cells, chondrocytes and osteoblasts (Cuervo et al, 2015) Although the specific mechanism of action of the platelet-rich products remains speculative, plateletrich products have been shown to promote the repair and remodelling of injured tissues, and to prevent cartilage degradation and atrophy of the periarticular structures (Anitua et al, 2013). The autologous nature of platelet-rich products, the ease of implementation and the relatively low cost are some of the qualities making this an attractive approach (Civinini et al, 2011). The procedure for preparation and administration of autologous platelets varies between manufacturers. Generally, a blood sample is taken and mixed with anticoagulant, although, in some systems, if the platelet concentrate is to be used immediately, the anticoagulant is not required. 3 / 11

4 The platelets are recovered from the blood using a variety of techniques. For example, one system adopts a point-of-use, gravity-dependent filter that takes approximately 15 minutes with no centrifugation required, while another uses a double syringe technique that requires centrifugation for five minutes. For administration of the platelet concentrate, arthrocentesis of the affected joint is performed to confirm positioning within the joint space before the platelet concentrate is injected into the joint (Figure 4). The volume of platelet concentrate injected also varies between manufacturers some recommend continuing to inject until sufficient intra-articular pressure is reached to push back the syringe plunger, while others advise 2.5ml per joint. The composition of various platelet-rich products available is a subject of considerable research (Dohan Ehrenfest et al, 2010). Four types of such products are possible: leukocyte-rich leukocyte-poor fibrin-present fibrin-absent (Fahie et al, 2013) Each of these may have more value in certain applications. For example, the presence of leukocytes could lead to deleterious effects, including inflammation (Boswell et al, 2012), in certain applications and to beneficial effects, such as infection-fighting capacity, in others (Bielecki et al, 2012). The concentration of platelets in the platelet-rich product also varies significantly between studies. These variations make comparison of different studies complex; however, there is a growing body of evidence supporting significant symptomatic improvement in dogs with OA-related pain following intra-articular administration of platelet-rich products based on subjective and objective measures. Examples of studies in human medicine include one by Wang-Saegusa et el (2011), where a significant improvement in function and quality of life was found in patients with OA of the knee at six months post-treatment. Sanchez et al (2008) compared the efficacy of intra-articular treatment with a platelet-rich product to hyaluronic acid and obtained more favourable results in the group treated with a platelet-rich product five weeks post-treatment. In the veterinary field, Kwon et al (2012) showed macroscopic and histological improvements in rabbits with OA treated with platelet-rich products and Serra et al (2013) found damaged tissue treated with autologous platelet-rich products showed a positive trend towards repair. 4 / 11

5 Figure 3. Preoperative mediolateral (A) and craniocaudal (B) radiographs of the right elbow of a five-year-old German shepherd dog with severe osteoarthritis secondary to medial coronoid process disease that underwent arthroscopic subtotal coronoidectomy bilaterally (C). The arthroscopic images show the eburnation of the cartilage with exposure of the subchondral bone in the medial compartment of the joint over the medial coronoid process (D) and extending up into the trochlear notch (E). In dogs, Fahie et al (2013) showed with OA involving a single joint, a single injection of intraarticular autologous platelets resulted in significant improvements after 12 weeks, as determined by subjective and objective (force plate analysis) measures. Franklin and Cook (2013) also demonstrated a significant improvement in lameness, activity and pain with elbow OA following intra-articular treatment with autologous conditioned plasma. Cuervo et al (2013) reported symptomatic improvements with OA of the elbow, hip and knee and Silva et al (2013) demonstrated after cranial cruciate ligament surgery there was no progression of OA changes in dogs treated with platelet-rich plasma. Mesenchymal stem cells Stem cells have generated enormous expectations and have become a great hope for the development of new cell therapies in the context of regenerative medicine (Diekman and Guilak, 2013; Fortier and Travis, 2011). Stem cells are undifferentiated cells with the ability to divide indefinitely without losing their properties and eventually produce specialised cells (Diekman and Guilak, 2013). Autologous adult stem cells are immunologically compatible, can be harvested from various sources and have no ethical issues related to their use (Black et al, 2007). Mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSCs) and adipose tissue (AD- MSCs) are the most highly characterised and considered comparable (Parker and Katz, 2006). Both have broad multipotency with differentiation in a number of cell lineages, including adipocytic, osteocytic and chondrocytic lineages (Parker and Katz, 2006). However, the easy and repeatable access to subcutaneous adipose tissue, the simple isolation procedure and the approximate 500-fold greater numbers of fresh MSCs derived from equivalent amounts of fat versus bone marrow provide a clear advantage for using AD-MSCs (Schaffler and Buchler, 2007; Fraser et al, 2006). The mechanisms of action of MSCs are multiple and exactly how they result in symptomatic improvement in cases of OA remains hotly debated. The immunomodulatory effects of BM-MSCs are well-documented and represent one therapeutic mechanism by which AD-MSCs may function (Gimble et al, 2007; Nasef et al, 2007; LeBlanc, 2006; Fang et al, 2007). 5 / 11

6 MSCs are known to secrete cytokines and growth factors, and may stimulate recovery in a paracrine manner (Gimble et al, 2007; Caplan and Dennis, 2006). BM-MSCs secrete interleukin-1 (IL-1) receptor antagonist, which was determined to be the specific mechanism reducing inflammation and fibrosis in a mouse model of injury (Oritz et al, 2007). Given the prominent role IL-1 plays in the cytokine cascade and joint disease, this is a likely mechanism by which MSCs may mediate their effect in canine OA (Black et al, 2007). Cell-based tissue regeneration may also play a role, similar to that noted in a rabbit model of osteochondral defects (Nathan et al, 2003). It is postulated AD-MSCs may engraft in synovium or in cartilaginous lesions and either influence the local cells to differentiate into cartilage or AD-MSCs themselves may differentiate into cartilage (Nathan et al, 2003; Black et al, 2007). Other studies dispute this and suggest an alternative hypothesis: when these MSCs are placed in an environment of injury, they express cytokines and growth factors that promote repair or activate compensatory mechanisms and endogenous stem cells within the tissue (Chopp et al, 2000). These trophic mechanisms are the prevailing theory regarding the clinical benefits attributed to stem cell therapy (Caplan and Dennis, 2006; Chopp et al, 2000). Isolation of cells from adipose tissue entails mincing and washing, followed by collagenase digestion and centrifugation (Gimble et al, 2007; Zuk et al, 2001). The pellet formed from centrifugation is deemed the stromal vascular fraction (SVF), which is resuspended and used as the treatment modality. The SVF contains a heterogeneous mixture of cells, including fibroblasts, pericytes, endothelial cells, circulating blood cells and AD-MSCs (Gimble et al, 2007; Varma et al, 2007; Yoshimura et al, 2006; Boquest et al, 2005). 6 / 11

7 Figure 4. Photograph showing arthrocentesis of the left stifle of a labradoodle being performed using aseptic technique to confirm positioning within the joint space prior to intraarticular injection. Veterinarians have been using autologous AD-MSCs to treat tendon and ligament disease in horses on a commercial basis since 2003 (Harman et al, 2006; Dahlgren, 2006; VetStem Inc, 2005). Data support improved healing in these tendon injuries with no significant systemic adverse effects and a very low incidence (0.5%) of local tissue reaction (Nixon et al, 2008; Dahlgren, 2006; VetStem Inc, 2005). Nathan et al (2003) demonstrated AD-MSCs in a fibrin carrier were able to fill osteochondral defects in a rabbit femoral condyle better than a fibrin carrier alone and the biomechanical performance of the AD-MSC-treated group was also superior. In a model of OA in the goat, BM-MSC therapy resulted in regeneration of the meniscal tissue and retardation of the normal progression of OA seen in the model with reduced degeneration of articular cartilage, osteophyte remodelling and subchondral bone sclerosis (Murphy et al, 2003). A placebo-controlled, double-blind study in dogs with hip OA demonstrated intra-articular AD-MSC therapy resulted in improved subjective orthopaedic examination scores in dogs, with lameness, range of motion and pain on manipulation improved relative to control animals (Black et al, 2007). Vilar et al (2014) demonstrated a single intra-articular administration of AD-MSC therapy decreased pain and lameness in dogs with hip OA based on objective force plate analysis. Taking into account the data on advanced therapies, it is clear autologous platelet therapy and 7 / 11

8 MSCs represent novel treatments generating high hopes in improving the structure and joint function in dogs with OA without the need for more aggressive techniques. Both techniques have been shown to ameliorate clinical signs associated with OA and demonstrated to improve the structural damage caused by the disease. While autologous platelet treatment probably has a shorter duration of effect, it has advantages of lower cost and being a less invasive technique, hence being more appropriate for outpatient use. Conclusion MSCs and autologous platelet therapy offer two additional options for canine patients that have failed to respond to more conventional treatment modalities. While more research needs to be performed in these areas to elucidate the exact mechanisms of action and durations of effect, these treatments are available and have satisfactory evidence to support their use. While salvage surgical options are available, these are associated with significant cost and potential complications and cellular therapies may offer an option, whereby surgical management can be either delayed or avoided without condemning the patient to a life of ongoing discomfort. References Anitua E et al (2013). A biological therapy to osteoarthritis treatment using platelet-rich plasma, Expert Opin Biol Ther b(8): 1,161-1,172. Beraud R et al (2010). Effect of exercise on kinetic gait analysis of dogs afflicted by osteoarthritis, Vet Comp Orthop Traumatol 23(2): Bielecki T et al (2012). The role of leukocytes from L-PRP/L-PRF in wound healing and immune defense: new perspectives, Curr Pharm Biotechnol 13(7): 1,153-1,162. Black LL et al (2007). Effect of adipose-derived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized double-blinded, multicenter controlled trial, Vet Ther 8(4): Boquest AC et al (2005). Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture, Mol Biol Cell 16(3): 1,131-1,141. Boswell SG et al (2012). Platelet-rich plasma: a milieu of bioactive factors, Arthroscopy 28(3): Caplan A and Dennis J (2006). Mesenchymal stem cells as trophic mediators, J Cell Biochemistry 98(5): 1,076-1,084. Chopp M et al (2000). Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation, Neuroreport 11(13): 3,001-3,005. Civinini R et al (2011). The use of autologous blood-derived growth factors in bone 8 / 11

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11 Powered by TCPDF ( van den Dolder J et al (2006). Platelet-rich plasma: quantification of growth factor levels and the effect on growth and differentiation of rat marrow cells, Tissue Eng 12(11): 3,067-3,073. Vandeweerd JM et al (2012). Systematic review of efficacy of nutraceuticals to alleviate clinical signs of osteoarthritis, J Vet Intern Med 26(3): Varma MJ et al (2007). Phenotypical and functional characterization of freshly isolated adipose tissue-derived stem cells, Stem Cells Dev 16(1): VetStem (2005). Data on file. Vilar JM et al (2014). Assessment of the effect of intra-articular injection of autologous adipose-derived mesenchymal stem cells in osteoarthritic dogs using a double blinded force platform analysis, BMC Vet Res 10: 143. Wang-Saegusa A et al (2011). Infiltration of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life, Arch Orthop Trauma Surg 131(3): Yoshimura K et al (2006). Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates, J Cell Phys 208(1): Zuk PA et al (2001). Multilineage cells from human adipose tissue: Implications for cellbased therapies, Tissue Eng 7(2): / 11