The most common orthopaedic developmental disease in dogs is hip dysplasia. This condition results in coxofemoral laxity due to incongruity and lack of stabilisation of the joint by the soft tissues. Currently, there is no therapeutic plan to correct hip dysplasia without surgical intervention at a very early age. The goal of the non-surgical treatment is to relieve pain and stiffness and to increase the muscle strength, usually through hydrotherapy and the beneficial physical properties of water. Recently, there has been growing interest in regenerative medicine, which involves the use of mesenchymal stem cells (MSCs) and their products to alleviate the characteristic clinical symptoms of osteoarthritis (OA). In vivo studies with canine MSCs have shown that an intra-articular injection of MSCs into cartilage lesions leads to the excellent regeneration of the hyaline cartilage. Regenerative medicine has undergone rapid development in recent years thanks to new therapies based on the application and combination of innovative biomaterials. One of the first known regenerative methods to be used in clinical practice was platelet-rich plasma (PRP). This review summarises the use and potential of MSCs and PRP, including their in vitro properties, their therapeutic effects in the treatment of cartilage lesions in preclinical in vivo studies, their clinical efficacy in the treatment of naturally occurring OA in dogs, and the current limitations of the studies.

Small Animal Clinic University of Veterinary Medicine and Pharmacy Košice Slovak Republic

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Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour AAA, Yousefi M, Talebi M, Shamsasenjan K. Regenerative potential of Wharton’s jelly-derived mesenchymal stem cells: A new horizon of stem cell therapy. J Cell Physiol. 2020 Dec;235(12):9230-40. PubMed

Alves R, Grimalt R. A review of platelet-rich plasma: History, biology, mechanism of action, and classification. Skin Appendage Disord. 2018 Jan;4(1):18-24. PubMed PMC

Bardens JW, Hardwick H. New observations on the diagnosis and cause of hip dysplasia. Vet Med Small Anim Clin. 1968 Mar;63(3):238-45. PubMed

Barlow TG. Early diagnosis and treatment of congenital dislocation of the hip. J Bone Joint Surg Br. 1962;44(2):292-301.

Barr ARS, Denny HR, Gibbs C. Clinical hip dysplasia in growing dogs: The long-term results of conservative management. J Small Anim Pract. 1987 Apr 1;28(4):243-52.

Beier JP, Bitto FF, Lange C, Klumpp D, Arkudas A, Bleiziffer O, Boos AM, Horch RE, Kneser U. Myogenic differentiation of mesenchymal stem cells co-cultured with primary myoblasts. Cell Biol Int. 2011 Apr;35(4):397-406. PubMed

Bergh MS, Budsberg SC. A systematic review of the literature describing the efficacy of surgical treatments for canine hip dysplasia. Vet Surg. 2014 Jul;43(5):501-6. PubMed

Black LL, Gaynor J, Gahring D, Adams C, Aron D, Harman S, Gingerich DA. 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(4):272-84. PubMed

Bland SD. Canine osteoarthritis and treatments: A review. Vet Sci Dev. 2015;5(2):84-9.

Bland IM, Guthrie-Jones A, Taylor RD, Hill J. Dog obesity: Owner attitudes and behaviour. Prev Vet Med. 2009 Dec;92(4):333-40. PubMed

Chalman JA, Butler HC. Coxofemoral joint laxity and the Ortolani sign. J Am Anim Hosp Assoc. 1985;21(5):671-6.

Chalmers HJ, Dykes NL, Lust G, Farese JP, Burton-Wuster NI, Williams AJ, Todhunter RJ. Assessment of bone mineral density of the femoral head in dogs with early osteoarthritis. Am J Vet Res. 2006 May;67(5):796-800. PubMed

Chandra V, Sharma GT. Prospects of mesenchymal stem cell secretome in veterinary regenerative therapy. In: Choudhary RK, Choudhary S, editors. Stem cells in veterinary science. Singapore: Springer; 2021. p. 271-87.

Cuervo B, Rubio M, Sopena J, Dominguez JM, Vilar J, Morales M, Cugat R, Carrillo JM. Hip osteoarthritis in dogs: A randomized study using mesenchymal stem cells from adipose tissue and plasma rich in growth factors. Int J Mol Sci. 2014;15(8):13437-60. PubMed PMC

da Costa VR, Araldi RP, Vigerelli H, D’Amelio F, Mendes TB, Gonzaga V, Policiquio B, Colozza-Gama GA, Valverde CW, Kerkis I. Exosomes in the tumor microenvironment: From biology to clinical applications. Cell. 2021 Oct 1;10(10):2617. PubMed PMC

de Haan JJ, Goring RL, Beale BS. Evaluation of polysulfated gllycosaminoglycan for the treatment of hip dysplasia in dogs. Vet Surg. 1994 May-Jun;23(3):177-81. PubMed

Desando G, Cavallo C, Sartoni F, Martini L, Parrilli A, Veronesi F, Fini M, Giardino R, Facchini A, Grigolo B. Intra-articular delivery of adipose derived stromal cells attenuates osteoarthritis progression in an experimental rabbit model. Arthritis Res Ther. 2013 Jan 29;15(1):R22. PubMed PMC

Domaniza M, Trbolova A, Hluchy M, Cizkova D. Mesenchymal stem cell-based treatment of osteoarthritis in dogs – A review. J Stem Cell Res Dev Ther. 2021 Oct;7(4):17.

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7. PubMed

Dycus D, Levine D, Marcellin-Little D. Physical rehabilitation for the management of canine hip dysplasia. Vet Clin Small Anim. 2017 Jul;47(4):823-50. PubMed

Eckert T, Jaehrling-Butkus M, Louton H, Burg-Roderfeld M, Zhang R, Zhang N, Siebert HC. Efficacy of chondroprotective food supplements based on collagen hydrolysate and compounds isolated from marine organisms. Mar Drugs. 2021 Sep 26;19(10):542. PubMed PMC

Eppley BL, Pietrzak WS, Blanton M. Platelet-rich plasma: A review of biology and applications in plastic surgery. Plast Reconstr Surg. 2006 Nov;118(6):147-59. PubMed

Frechette JP, Martineau I, Gagnon G. Plateletrich plasmas: Growth factor content and roles in wound healing. J Dent Res. 2005 May;84(5):434-9. PubMed

Fujiki M, Kurima Y, Yamanokuchi K, Misumi K, Sakamoto H. Computed tomographic evaluation of growth-related changes in the hip joints of young dogs. Am J Vet Res. 2007 Jul;68(7):730-4. PubMed

Ghosh P, Smith M, Wells C. Second-line agents in osteoarthritis. In: Dixon JS, Furst DE, editors. Second-line agents in the treatment of rheumatic diseases. New York: Marcel Dekker; 1993. p. 363-427.

Gimble JM, Guilak F, Nuttall ME, Sathishkumar S, Vidal M. In vitro differentiation potential of mesenchymalstemcells. Transfus Med Hemother. 2008 Jun;35(3): 228-38. PubMed PMC

Ginja MMD, Ferreira AJ, Jesus SS, Melo-Pinto P, Bulas-Cruz J, Orden MA, Gonzalo-Orden JM. Comparison of clinical, radiographic, computed tomographic and magnetic resonance imaging methods for early prediction of canine hip dysplasia. Vet Radiol Ultrasound. 2009 Mar-Apr;50(2):135-43. PubMed

Ginja MMD, Silvestre AM, Gonzalo-Orden JM, Ferreira AJA. Diagnosis, genetic control and preventive management of canine hip dysplasia: A review. Vet J. 2010 Jun;84(3):269-76. PubMed

Guo W, Douma L, Hu MH, Eglin D, Alini M, Secerovic A, Grad S, Peng X, Zou X, D’Este M, Peroglio M. Hyaluronic acid-based interpenetrating network hydrogel as a cell carrier for nucleus pulposus repair. Carbohydr Polym. 2022 Feb 1;277:118828. PubMed

Harting MT, Jimenez F, Xue H, Fischer UM, Baumgartner J, Dash PK, Cox CS. Intravenous mesenchymal stem cell therapy for traumatic brain injury. J Neurosurg. 2009 Jun;110(6):1189-97. PubMed PMC

Henry GA. Radiographic development of canine hip dysplasia. Vet Clin North Am Small Anim Pract. 1992 May;22(3):559-78. PubMed

Hunakova K, Hluchy M, Spakova T, Matejova J, Mudronova D, Kuricova M, Rosocha J, Ledecky V. Study of bilateral lake joint osteoarthritis treatment using conditioning medium from allogeneic adipose tissue-derivedMSCs in Labrador Retrievers. Res Vet Sci. 2020 Oct 1;132:513-20. PubMed

Hussain N, Johal H, Bhandari M. An evidence-based evaluation on the use of platelet rich plasma in orthopedics – A review of the literature. SICOT J. 2017;3:57. PubMed PMC

Ivanovska A, Wang M, Arshaghi TE, Shaw G, Alves J, Byrne A, Butterworth S, Chandler R, Cuddy L, Dunne J, Guerin S, Harry R, McAlindan A, Mullins RA, Barry F. Manufacturing mesenchymal stromal cells for thetreatment of osteoarthritis in canine patients: Challenges and recommendations. Front Vet Sci. 2022 Jun;9:897150. PubMed PMC

Joseph A, Baiju I, Bhat IA, Pandey S, Bharti M, Verma M, Pratap Singh A, Ansari MM, Chandra V, Saikumar G, Amarpal A, Sharma GT. Mesenchymal stem cell-conditioned media: A novel alternative of stem cell therapy for quality wound healing. J Cell Physiol. 2020 Jan;235(12):5555-69. PubMed

Kang MH, Park HM. Evaluation of adverse reactions in dogs following intravenous mesenchymal stem cell transplantation. Acta Vet Scand. 2014 Mar;56(1):16. PubMed PMC

Kay AG, Long G, Tyler G, Stefan A, Broadfoot SJ, Piccinini AM, Kehoe O. Mesenchymal stem cell-conditioned medium reduces disease severity and immune responses in inflammatory arthritis. Sci Rep. 2017;7(1):18019. PubMed PMC

Kiefer KM, O’Brien TD, Pluhar EG, Conzemius M. Canine adipose-derived stromal cell viability following exposure to synovial fluid from osteoarthritic joints. Vet Rec Open. 2015 Jul;2(1):e000063. PubMed PMC

Kirkby KA, Lewis D. Canine hip dysplasia: Reviewing the evidence for nonsurgical management. Vet Surg. 2012 Jan;41(1):2-9. PubMed

Kriston-Pal E, Czibula A, Gyuris Z, Balka G, Seregi A, Sukosd F, Suth M, Kiss-Toth E, Haracska L, Uher F, Monostori E. Characterization and therapeutic application of canine adipose mesenchymal stem cells to treat elbow osteo-arthritis. Can J Vet Res. 2017 Jan;81(1):73-8. PubMed PMC

Lee HR, Shon OJ, Park SI, Kim HJ, Kim S, Ahn MW, Do SH. Platelet-rich plasma increases the levels ofcatabolic molecules and cellular dedifferentiation in the meniscus of a rabbit model. Int J Mol Sci. 2016 Jan;17(1):120. PubMed PMC

Lust G, Williams AJ, Burton-Wurster N, Beck KA, Rubin G. Effects of intramuscular administration of glycosaminoglycan polysulfates on signs of incipient hip dysplasia in growing pups. Am J Vet Res, 1992 Oct;53(10):1836-43. PubMed

Madsen JS, Reimann I, Svalastoga E. Delayed ossification of the femoral head in dogs with hip dysplasia. J Small Anim Pract. 1991 Jul;32:351-4.

Maki CB, Beck A, Wallis C, Choo J, Raos T, Tong R, Borjesson DL, Izadyar F. Intra-articular administration of allogeneic adipose derived mscs reduces pain and lameness in dogs with hip osteoarthritis: A double blinded, randomized, placebo controlled pilot study. Front Vet Sci. 2020 Aug;7:570. PubMed PMC

Manley PA, Adams WM, Danielson KC, Dueland RT, Linn KA. Long-term outcome of juvenile pubic symphysiodesis and triple pelvic osteotomy in dogs with hip dysplasia. J Am Vet Med Assoc. 2007 Jan;230(2):206-10. PubMed

McGowan C, Goff L. Canine therapy and rehabilitation for orthopaedic conditions. In: Goff S, Stubbs N, editors. Animal physiotherapy: Assessment, treatment and rehabilitation of animals. 2nd ed. Chichester, West Sussex: Wiley-Blackwell; 2016a. p. 272-301.

McGowan C, Goff L. Aquatic theray. In: Goff S, Stubbs N, editors. Animal physiotherapy: Assessment, treatment and rehabilitation of animals. 2nd ed. Chichester, West Sussex: Wiley-Blackwell; 2016b. p. 225-37.

Miki S, Takao M, Miyamoto W, Matsushita T, Kawano H. Intra-articular injection of mesenchymal stem cell-derived synovial hyaluronic acid can repair articular cartilage defects in a canine model. J Stem Cell Res Ther. 2015 Jan;5(11).

Milano G, Sanna Passino E, Deriu L, Careddu G, Manunta L, Manunta A, Saccomanno MF, Fabbriciani C. The effect of platelet rich plasma combined with microfractures on the treatment of chondral defects: An experimental study in a sheep model. Osteoarthritis Cartilage. 2010 Jul;18(7):971-80. PubMed

Millis DL, Levine D. Canine rehabilitation and physical therapy. 2nd ed. Philadelphia: Elsevier Health Sciences; 2014. 784 p.

Mokbel AN, El Tookhy OS, Shamaa AA, Rashed LA, Sabry D, El Sayed AM. Homing and reparative effect of intra-articular injection of autologus mesenchymal stem cells in osteoarthritic animal model. BMC Musculoskelet Disord. 2011 Nov 15;12:259. PubMed PMC

Olsen A, Johnson V, Webb T, Santangelo KS, Dow S, Duerr FM. Evaluation of intravenously delivered allogeneic mesenchymal stem cells for treatment of elbow osteoarthritis in dogs: A pilot study. Vet Comp Orthop Traumatol. 2019 May;32(3):173-81. PubMed

Ozeki N, Muneta T, Koga H, Nakagawa Y, Mizuno M, Tsuji K, Mabuchi Y, Akazawa C, Kobayashi E, Matsumoto K, Futamura K, Saito T, Sekiya I. Not single but periodic injections of synovial mesenchymal stem cell maintain viable cells in knees and inhibit the progression of osteoarthritis in rats. Osteoarthritis Cartilage. 2016 Jun;24(6):1061-70. PubMed

Prydie D, Hewitt I. Modalities. In: Prydie D, Hewitt I, editors. Practical physiotherapy for small animal practice. 1st ed. West Sussex: Wiley-Blackwell; 2015a. p. 69-90.

Prydie D, Hewitt I. Treatment protocols for hip dysplasia. In: In: Prydie D, Hewitt I, editors. Practical physiotherapy for small animal practice. 1st ed. West Sussex: Wiley-Blackwell; 2015b. p. 237-40.

Pye C, Bruniges N, Peffers M, Comerford E. Advances in the pharmaceutical treatment options for canine osteoarthritis. J Small Anim Pract. 2022 Mar;63(10):721-38. PubMed PMC

Riser WH. The dog as a model for the study of hip dysplasia: Growth, form, and development of normal and dysplastic hip joint. Vet Pathol. 1975;12(4):244-334. PubMed

Robertson ID. The association of exercise, diet and other factors with owner perceived obesity in privately owned dogs from metropolitan perth. Prev Vet Med. 2003 Apr;58(1-2):75-83. PubMed

Sabry D, Shamaa A, Amer M, El-Tookhy O, Abdallah A, Abd El Hassib DM, Amer E, Elamir A. The effect of mesenchymal stem cell derived microvesicles in repair of femoral chondral defects in dogs. J Musculoskelet Res. 2018;21(2):1850006.

Samoy Y, Van Ryssen B, Saunders J. Physiotherapy in small animal medicine. Vlaams Diergeneeskundig Tijdschrift. 2018;85:323-34.

Sampson S, Gerhardt M, Mandelbaum B. Platelet rich plasma injection grafts for musculoskeletal injuries: A review. Curr Rev Musculoskelet Med. 2008 Dec;1(3-4):165-74. PubMed PMC

Sampson S, Reed M, Silvers H, Meng M, Mandelbaum B. Injection of platelet-rich plasma in patients with primary and secondary knee osteoarthritis: A pilot study. Am J Phys Med Rehabil. 2010 Dec;89(12):961-9. PubMed

Sasaki A, Mizuno M, Mochizuki M, Sekiya I. Mesenchymal stem cells for cartilage regeneration in dogs. World J Stem Cells. 2019 May;11(5):254-69. PubMed PMC

Satue M, Schueler C, Ginner N, Erben RG. Intra-articularly injected mesenchymal stem cells promote cartilage regeneration, but do not permanently engraft in distant organs. Sci Rep. 2019 Jul;9(1):10153. PubMed PMC

Schachner ER, Lopez MJ. Diagnosis, prevention, and management of canine hip dysplasia: A review. Vet Med (Auckl). 2015 May 19;6:181-92. PubMed PMC

Sharp B. Physiotherapy in small animal practice. In Pract. 2008 Apr;30(4):190-9.

Sharun K, Dhama K, Jambagi K, Pawde AM. Cell-free therapy for inflammatory diseases: opportunities and challenges. Recent Adv Inflamm Allergy Drug Discov. 2022;15(1):5-8. PubMed

Simental-Mendia M, Lozano-Sepulveda SA, Perez-Silos V, Fuentes-Mera L, Martinez-Rodriguez HG, Acosta-Olivo CA, Pena-Martinez VM, Vilchez-Cavazos F. Anti-inflammatory and anti-catabolic effect of non-animal stabilized hyaluronic acid and mesenchymal stem cell-conditioned medium in an osteoarthritis coculture model. Mol Med Rep. 2020 May;21(5):2243-50. PubMed

Stief M, Gottschalk J, Ionita JC, Einspanier A, Oechtering G, Boettcher P. Concentration of platelets and growth factors in canine autologous conditioned plasma. Vet Comp Orthop Traumatol. 2011 Jan;24(2):122-5. PubMed

Tao SC, Yuan T, Zhang YL, Yin WJ, Guo SC, Zhang CQ. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics. 2017 Jan 1;7(1):180-95. PubMed PMC

Tofino-Vian M, Guillen MI, Alcaraz MJ. Extracellular vesicles: A new therapeutic strategy for joint conditions. Biochem Pharmacol. 2018 Jul;153:134-46. PubMed

Usha PR, Naidu MUR. Randomized, double-blinded parallel, placebo-controlled study of oral glucosamin, methylsulfonylmethane and their combination in osteoartritis. Clin Drug Invest. 2004;24(6):353-63. PubMed

Vezzoni A, Dravelli G, Corbari A, De Lorenzi M, Cirla A, Tranquilo V. Early diagnosis of canine hip dysplasia. Eur J Comp Anim Pract. 2005;15:173-83.

Vilar JM, Batista M, Morales M, Santana A, Cuervo B, Rubio M, Carrillo JM. Assessment of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells in osteoarthritic dogs using a double blinded force platform analysis. BMC Vet Res. 2014 Jul 1;10:143. PubMed PMC

Vilar JM, Cuervo B, Rubio M, Sopena J, Dominguez JM, Santana A, Carrillo JM. Effect of intraarticular inoculation of mesenchymal stem cells in dogs with hip osteoarthritis by means of objective force platform gait analysis: Concordance with numeric subjective scoring scales. BMC Vet Res. 2016 Oct;12(1):223. PubMed PMC

Vilar JM, Morales M, Santana A, Spinella G, Rubio M, Cuervo B, Cugat R, Carrillo JM. Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs. BMC Vet Res. 2013 Jul 2;9:131. PubMed PMC

Wang H, Shan XB, Qiao YJ. PDK2 promotes chondrogenic differentiation of mesenchymal stem cells by upregulation of Sox6 and activation of JNK/MAPK/ERK pathway. Braz J Med Biol Res. 2017 Feb;50(2):e5988. PubMed PMC

Whitworth DJ, Banks TA. Stem cell therapies for treating osteoarthritis: Prescient or premature? Vet J. 2014 Dec;202(3):416-24. PubMed

Wong E. Hip dysplasia. In: Wong E, editor. Swim to recovery: Canine hydrotherapy healing. 1st ed. Dorchester, England: Hubble & Hattie; 2011. p. 55-69.

Wu FM, Hedhammar A, Krook L. Overnutrition and skeletal disease. An experimental study in growing Great Dane dogs. IX. The long bones. Cornell Vet. 1974 Apr;64(2):Suppl_5:83-114. PubMed

Zeng Z, Dai Y, Deng S, Zou S, Dou T, Wei F. Synovial mesenchymal stem cell-derived extracellular vesicles alleviate chondrocyte damage during osteoarthritis through microRNA-130b-3p-mediated inhibition of the LRP12/AKT/β-catenin axis. Immunopharmacol Immunotoxicol. 2022 Jan;44(2):247-60. PubMed

Zhang BY, Wang BY, Li SC, Luo DZ, Zhan X, Chen SF, He Y. Evaluation of the curative effect of umbilical cord mesenchymal stem cell therapy for knee arthritis in dogs using imaging technology. Stem Cells Int. 2018 May;1:1983025. PubMed PMC

Zhao C, Chen JY, Peng WM, Yuan B, Bi Q, Xu YJ. Exosomes from adipose-derived stem cells promote chondrogenesis and suppress inflammation by upregulating miR-145 and miR-221. Mol Med Rep. 2020 Apr;21(4):1881-9. PubMed PMC

Zink C, Van Dyke JB. Canine sports medicine and rehabilitation. 1st ed. Ames, Iowa: Wiley-Blackwell; 2013. p. 159-75.