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Ortved Laboratory

The Ortved Laboratory at New Bolton Center is focused on understanding the pathophysiology of post-traumatic osteoarthritis (PTOA) and developing gene and cell-based therapies to help regenerate cartilage and prevent the development of PTOA following joint injury.

Due to the many similarities in joint biomechanics and propensity for PTOA, our lab uses the horse as a large animal model for human joint disease. Our goal is to develop translational regenerative therapies that would benefit both the equine and human patient.

Lab Mission

  • To improve cartilage repair using stem cell and gene therapy.
  • To limit the long-term effects of joint trauma through gene therapy immunomodulation of the joint.
  • To further elucidate the pathogenesis of post-traumatic osteoarthritis (PTOA).

Dr. Kyla Ortved, New Bolton Center

Interested in Working With Us?

We are always seeking highly motivated students and post-doctoral fellows with an interest in:

  • Orthopedic research
  • Joint disease
  • Stem cell therapy
  • Gene therapy
  • Regenerative medicine
  • Cartilage biology

Contact: Dr. Kyla Ortved at kortved@vet.upenn.edu

Contact Information

Dr. Kyla Ortved, New Bolton Center

Kyla Ortved, DVM, PhD, DACVS, DACVSMR

New Bolton Center
382 W. Street Road
Kennett Square, PA

Joint injuries are overwhelmingly common in both human and equine athletes. Chondrocytes, the sole cell type in cartilage, are responsible for producing and maintaining the extra-cellular matrix (ECM), which affords remarkable tensile and compressive strength to the joint surface. Once damaged, cartilage has little to no ability to heal itself. Therefore, posttraumatic osteoarthritis (PTOA) commonly develops following sufficient joint trauma, whether sustained during an acute injury or accumulated overtime.

Unfortunately, PTOA is a progressive, debilitating disease that currently lacks any effective treatment. Pain and decreased mobility are addressed with systemic non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, rest and rehabilitation. The end stage therapy for OA joints in humans is total joint replacement, while select joints in the horse can be treated with surgical arthrodesis. Both of these procedures are invasive and expensive interventions.

Our lab is focused on understanding the pathogenesis of PTOA and developing regenerative medicine therapies to help regenerate cartilage and prevent the development of PTOA following joint injury. Specifically, we are interested in gene and cell therapies targeted at reducing post-traumatic inflammation and improving repair of the articular surface, thereby preventing the development of PTOA in the first place. Dr. Ortved’s clinical work as an equine orthopedic surgeon facilitates translation of this research from bench to clinic floor.

Dr. Kyla Ortved in surgery, New Bolton Center

Research Techniques

  • Cell culture of equine mesenchymal stem cells
  • Molecular biology: PCR and qRT-PCR, flow cytometry, protein analysis
  • Microscopy
  • Histology

Stem cell therapy

Cell-based therapies aim to return damaged or injured tissue to a more normal structure and function. An overarching goal in cell-based repair is to restore the articular surface, thereby preventing further joint degradation. Although bone marrow-derived MSCs (BM-MSCs) have been the most frequently used MSC type for cartilage repair to date, full chondrogenic differentiation has been disappointing. Therefore, we are currently investigating the chondrogenic differentiation capability of synovial membrane-derived mesenchymal stem cells (SD-MSCs). Recent experiments using flow cytometry in the Ortved laboratory have demonstrated a similar immunophenotype between BM-MSCs and SD-MSCs, with SD-MSCs expressing the appropriate markers of stemness. We have also shown that SD-MSCs have increased proliferative capacity in vitro, making timely culture expansion of these cells achievable. The ultimate goal of this research is defining a source of adult MSCs suitable for resurfacing cartilage lesions to facilitate healing.

harvesting bone marrow, Dr. Kyla Ortved, New Bolton Center
 Caption: Bone marrow is harvested from the sternum of a sedated horse and culture-expanded in the lab.  We are using these cells to form cartilage- like pellets through chondrogenic differentiation, in order to optimize a cell-source that could be used to repair cartilage defects in the joint.

 

Gene Therapy

Gene therapy also has the potential to bolster the weak healing response in articular cartilage. Dr. Ortved has demonstrated improved cartilage repair in large, full-thickness chondral defects created in the lateral trochlear ridge of the equine femur using autologous chondrocytes transduced ex vivo with an adeno-associated virus (AAV) vector overexpressing the anabolic protein IGF-I.

Arthroscopic images of empty (a), implanted (b) and healing defects 8 weeks postimplantation (c-f)
Caption: Arthroscopic images of empty (a), implanted (b) and healing defects 8 weeks postimplantation (c-f). (c) Defects repaired with rAAV5-IGF-I transduced chondrocytes had better defect fill and white “cartilage- like” tissue compared to the defects filled with (d) rAAV5-GFP transduced chondrocytes, (e) untransduced chondrocytes, or (f) fibrin alone.

 

Dr. Ortved has also demonstrated that AAV vectors can be used to safely transduce equine articular cells in vivo with efficient, sustained expression of a therapeutic transgene. More recently, Dr. Ortved has been investigating AAV-mediated overexpression of interleukin-10 (IL-10), an immunomodulatory cytokine. She showed that L-10 overexpression downregulates expression of proinflammatory mediators in inflamed chondrocytes in vitro. We are now beginning to assess the effects of this therapy in vivo to determine if it can mitigate the post- traumatic inflammatory response that occurs following joint injury.

Dr. Kyla Ortved, New Bolton Center, Microscopy
Caption: Equine chondrocytes have been transduced with an AAV vector expressing red fluorescent protein.
 

Post-traumatic Osteoarthritis (PTOA)

We are investigating changes in gene expression in cartilage, synovium, fat pad and meniscus in horses with PTOA, in order to understand how different pathways are affected by trauma. We are also developing an ex vivo model of PTOA to help understand the histologic, microscopic and molecular changes that occur post-traumatically.

 
  1. Ortved KF, Witte S, Fleming K, Nash J, Woolums AR, Peroni JF. Laparoscopic-assisted splenectomy in a horse. Equine Vet Educ 20: 357-361, 2008.
  2. Ortved KF, Krotscheck U, Collins SA, Rawlinson JJ, Dyce J. Cementless total hip replacement in an alpaca. Vet Surg 38:583-587, 2009.
  3. Ortved KF, Cheetham J, Mitchell LM, Ducharme NG. Successful treatment of persistent dorsal displacement of the soft palate and evaluation of laryngohyoid position in 15 racehorses. Equine Vet J 42:23-29, 2010.
  4. Ortved KF, Nixon AJ, Mohammed HO, Fortier LA. Treatment of subchondral bone cysts of the medial femoral condyle in mature horses with growth factor enhanced chondrocyte grafts: A retrospective study of 49 cases. Equine Vet J 44:606-613, 2012.
  5. Ortved KF, Stewart AW, Fubini SL, Hackett RP. Surgical treatment of 4 horses for cryptorchidism caused by failure of regression of the cranial suspensory ligament of the testis. Vet Surg 43: 266-270, 2014.
  6. Ortved KF, Begum L, Mohammed HO, Nixon AJ. Implantation of rAAV5-IGF-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model. Molecular Therapy, 23:363-373, 2015.
  7. Ortved KF, Wagner B, Calcedo R, Wilson JM, Schaefer DM, Nixon AJ. Humoral and cell-mediated immune response, and growth factor synthesis after direct intra-articular injection of rAAV2-IGF-I or rAAV5-IGF-I in the equine middle carpal joint. Human Gene Therapy, 26:161-171, 2015.
  8. Griffin  D, Ortved KF, Nixon AJ, Bonassar L. Mechanical properties and structure- function relationships in articular cartilage repair using IGF-I gene therapy. Journal of Orthopedic Research, 34:149-153, 2016.
  9. Ortved KF, Austin BS,  Scimeca MS, Nixon  AJ. RNA interference mediated interleukin-1β silencing in inflamed chondrocytes decreases target and downstream catabolic responses. Arthritis 2016: 3484961, 2016.
  10. Ortved KF, Nixon AJ. Cell-based cartilage repair strategies for horses. Vet J 208:1-12, 2016.
  11. Ortved KF, Goodale MB, Ober C, Maylin GA, Fortier LA. Plasma firocoxib concentrations after intra-articular injection of autologous conditioned serum prepared from firocoxib positive horses. Vet J, 2017.
  12. Ortved KF. Surgical management of osteochondrosis in foals. Vet Clin North Am Eq Pract 33:379-396, 2017.
 
 
Ortved Lab
Dr. Kyla Ortved, New Bolton Center 

Kyla Ortved, DVM, PhD, DACVS, DACVSMR

  • Assistant Director of Large Animal Surgery
  • Director of the Ortved Lab

Kyla is an assistant professor of Large Animal Surgery at New Bolton Center, the large animal campus of the University of Pennsylvania School of Veterinary Medicine, located in Kennett Square, Pennsylvania. She received her DVM  degree from the University of Guelph  in 2006  and completed her large  animal  surgical residency at Cornell University in 2010.  Following her residency, Dr. Ortved went on to obtain a PhD in equine cartilage repair at Cornell University in June 2014. She has a long-standing interest in the development, prevention and treatment of post-traumatic osteoarthritis and is excited by the translational nature of this research between veterinary and human medicine.

Renata Linardi, Ortved Lab

Renata Linardi, DVM, MS, PhD

  • Research specialist
  • Lab manager
 Renata is a research specialist and lab manager in the Ortved lab. Renata received her DVM  degree from Universidade Estadual Paulista-UNESP in Brazil in 2000.  Following veterinary school  she completed a residency in large  animal  anesthesiology and surgery. Renata then went on to obtain a PhD in pharmacology and molecular  biology from Louisiana State University in 2010.  After completion of graduate school, she came  to New Bolton Center, University of Pennsylvania to complete a post doc. She joined the Ortved lab as a research specialist and lab manager in 2016.  In her free time, Renata enjoys  spending time with her family.
Alexis Gale, Ortved Lab

Alexis Gale, BSc

  • Research fellow
 Alexis is a research assistant in Dr. Kyla Ortved’s lab at the University of Pennsylvania School of Veterinary Medicine. She graduated from Cornell University with a bachelor’s degree in animal science in 2017. Her research at both Cornell and Penn has involved prevention of osteoarthritis in horses. She intends to pursue both a veterinary degree and a PhD in the near future and continue to study equine orthopedics. She is also interested in how techniques used in equine medicine can be applied to human medicine. In her spare time, she enjoys polo, running, and hiking.