Introduction

Osteoarthritis is a degenerative condition of the synovial joint caused by complex biological and biochemical interactions and characterised by articular cartilage degeneration and inappropriate repair, osteophyte formation and subchondral bone remodelling, synovial membrane inflammation, periarticular tissue pathology and low-grade inflammation within the joint itself. The condition is irreversible and often results in end-stage joint disease. Approximately 20% of adult dogs are affected at any one time, usually secondarily to structural, functional or traumatic joint abnormality.¹

The joint inflammation and cartilage damage associated with the condition leads to pain and disability. Current treatment regimes rely on a multimodal approach including pain relief, weight management, nutritional management, exercise modulation and physical therapy. Advanced therapies are new treatments that focus on regenerative medicine, aiming to regenerate or repair the damaged joint. Cellular therapies act within the joint itself whilst targeted molecular therapies are being developed to relieve the pain and inflammation associated with the condition whilst avoiding the potential side effects of current drug therapies, especially non-steroidal anti- inflammatories (NSAIDs).

Autologous Platelet Therapy

The intra-articular injection of autologous platelets is a potentially promising new therapy for OA in dogs. Platelets contain growth factors that have been shown to enhance regenerative processes in osteoarthritic joints. Growth factors including platelet derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), transforming growth factor BETA, basic fibroblast growth factor bFGF and platelet factor-4) are found in the alpha granules of platelets and have been reported to both directly promote healing and recruit stem cells to local sites facilitating repair.²

Intra-articular injection of autologous platelets is a generally low-cost, easy procedure that requires blood sampling, platelet extraction and then injection into the affected joint. Relatively few cases are reported in the veterinary literature with more evidence available in human medicine. In one study of dogs with OA in a single joint, injection of autologous platelets resulted in significant improvement in lameness 12 weeks later, both subjectively and objectively.³

Mesenchymal Stem Cells

Stem cells are gaining increasing popularity for use in regenerative techniques. Stem cells are undifferentiated cells with the ability to divide indefinitely without losing their properties and will eventually develop to produce specialised cell lines. Autologous adult stem cells are compatible immunologically and there are no ethical concerns regarding their use. They are derived from bone marrow or adipose tissue with the latter being the most accessible and containing significantly more stem cells per gram of tissue.⁴ Isolation of the cells involves harvesting adipose tissue, mincing, washing, collagenase digestion and centrifugation. The pellet formed is re-suspended and used for the treatment.

In equine medicine there are a number of reports advocating the use of stem cells for ligament and tendon injuries with no adverse systemic effects and minimal local tissue reaction. A couple of canine studies have identified improved orthopaedic examination scores in dogs being treated with intra-articular mesenchymal stem cells for OA.⁵

Grapiprant

A more-targeted approach than the use of NSAIDs for treating OA would involve blockage of only the part of the prostaglandin pathway involved in pain and inflammation without altering the protective mechanisms of that pathway. Prostaglandin E2 is the most abundant prostaglandin in synovia and is pivotal in the development of joint inflammation and pain.⁶ Four PGE2 receptors exist with the EP4 receptor being identified specifically as the one mediating pain and inflammation in experimental OA in rodents.⁶

Grapiprant is a new analgesic and anti-inflammatory drug of the piprant class and is a highly potent and selective antagonist of the PGE2 EP4 receptor in rodents, humans and dogs.⁷ FDA approval has been granted for the drug for use in the treatment of the pain and inflammation linked to OA and it will be available in the U.S. in Autumn 2016.

Diacerin

Symptomatic slow-acting drugs for osteoarthritis are agents that provide symptomatic relief of OA by targeting the underlying pathology in cartilage and subchondral bone, whilst causing fewer side effects than NSAIDs. Diacerin is one of these drugs and has anti-inflammatory, analgesic and antipyretic effects. The drug also demonstrates IL-1BETA inhibitory properties, reducing the pro-inflammatory effects of the cytokine. A meta- analysis of controlled clinical studies in treatment of OA in humans has provided statistically significant and clinically relevant efficacy of Diacerein for improving pain and function in patients with OA to a similar level as those seen with NSAID treatment.⁸

Anti-nerve Growth Factor Antibody

Nerve growth factor (NGF) is required in the adolescent nervous system for development and maintenance of sensory and sympathetic neurons. In adults, the growth factor has been identified as pro-nociceptive with modulatory effects on the tyrosine-kinase receptor and is involved in the sensation of pain including that of OA.⁹ In canine studies, anti-NGF antibodies have been demonstrated to alleviate pain in dogs with OA for up to four weeks.⁹ Whilst numbers in these trials are low (35 dogs in total) and adequate information regarding side effects and long-term effects are lacking, this may be a further useful adjunct to the management of OA in the canine patient.

Conclusion

Whilst NSAIDs are the current mainstay of treatment in OA patients, concerns about side-effects and their long-term use exist. Furthermore they do not always manage the signs of OA adequately and adjunctive therapies are often necessary. Whilst salvage surgeries including joint replacement are available to treat end-stage cases of joint disease, they are aggressive procedures that are not without complications. Developing methods of treatment that repair and regenerate the damaged joint tissues or provide targeted therapy could dramatically improve the options for conservative management available to veterinarians and improve the long-term outlook for many of our patients.

References

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2.  Cuervo B, Rubio M, Cugat R, et al. New approaches in the treatment of osteoarthritis. Int J Ortho. 2015;23:210–218.

3.  Fahie MA, Ortolano GA, Guercio V, et al. A randomized controlled trial of the efficacy of autologous platelet therapy for the treatment of osteoarthritis in dogs. J Am Vet Med Assoc. 2013;243:1291–1297.

4.  Schaffler A, Buchler C. Concise review: adipose tissue-derived stem cells - basic and clinical implications for novel cell-based therapies. Stem Cells. 2007;25:818–827.

5.  Black LL, Gaynor J, Gahring D, et al. 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. 2007;8:272–284.

6.  Clark P, Rowland DE, Denis D, et al. MF498 [N-{14-(5,9-diethoxy-6-oxo- 6,8-dihydro-7 Hpyrrolo[3,4g]quinolin-7-yl)-3-methylbenzyl]sulfonyl)-2-(2- methoxyphenyl)acetamide], a selective E prostanoid receptor 4 antagonist, relieves joint inflammation and pain in rodent models of rheumatoid and osteoarthritis. J Pharmacol Exp Ther. 2008;325:425–434.

7.  Nakao K, Murase A, Oshiro H, et al. CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther. 2007;322:686–694. and RaQualia

8.  Rintelen B, Neumann K, Leeb BF. A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis. Arch Intern Med. 2006;166:1899–1906.

9.  Lascelles BDX, Knazovicky D, Case B, et al. A canine-specific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain. BMC Vet Res. 2015;11:101.