This proposal describes a five year training program to prepare the applicant for a career as an independent researcher in comparative orthopaedics. The principal investigator holds a veterinary degree, and obtained his PhD in the field of comparative and experimental medicine. He has extensive surgical training, is a member of the American College of Veterinary Surgeons, and is currently employed as a postdoctoral fellow studying osteochondrosis (OC) using high field MRI techniques at the University of Minnesota. The proposed research aims to further our understanding of the pathogenesis, and enhance diagnosis and treatment of OC, a developmental orthopaedic disease that primarily affects young athletes. Osteochondrosis is characterized by the formation of loose, intra-articular (osteo)cartilaginous fragments, which, if left untreated, commonly result in osteoarthritis later i life. Dr. Cathy Carlson, a veterinary pathologist and internationally recognized expert on OC, will serve as the primary mentor of the candidate. Dr. Carlson is the director of an institutional training grant (T32OD010993, Comparative Medicine and Pathology Training) and has trained numerous graduate students. Due to the multidisciplinary nature of the proposed studies, two additional co-mentors with various fields of expertise are included in the mentoring team: Dr. Michael Garwood, professor of radiology, Associate Director of the Center for Magnetic Resonance Research, which is a world renowned high field MRI research facility; and Dr. Denis Clohisy, professor and chairman, Department of Orthopedic Surgery. Dr. Troy Trumble, Associate Professor, Department of Veterinary Population Medicine will serve as a collaborator during the award period. This group of mentors and collaborator will ensure that the candidate will gain sufficient experience with: 1) the use of animal models of human disease; 2) histological techniques used to evaluate musculoskeletal tissues; 3) grantsmanship skills; 4) current and developing techniques in musculoskeletal MRI; 5) evaluation of biomarkers of orthopedic disease; and 6) advanced clinical and teaching techniques. Research will be focused on three aims: 1.) characterization of vascular architecture at predilection sites of OC 2.) development of a goat model of human OC 3.) validation of novel MRI techniques and identification of biomarkers capable of diagnosing osteochondrosis in the early, subclinical stage. To achieve the first aim, predilection sites and non-predilection sites of OC will be imaged using novel MRI sequences. To achieve our second aim, vascular supply to the epiphyseal cartilage of a well-defined area of the distal femur will be surgically interrupted in juvenile goas to create an area of cartilage necrosis (chondronecrosis), characteristic of subclinical osteochondrosis. Successful induction of this lesion will be evaluated by repeated imaging of the operated joint and by histological and immunohistochemical evaluation of joint samples obtained after euthanasia. During completion of the third aim, ability of novel MRI sequences to identify areas of the epiphyseal cartilage that have decreased vascular supply and areas of diminished proteoglycan and collagen content typical of early osteochondrosis lesions will be evaluated. Surgically induced lesions will be evaluated in goats and naturally occurring disease will be investigated in pigs. To validate MRI findings, samples will be processed for histology and serially sectioned in a plane matching that of the MRI scans. Sections (special stains and immunohistochemistry preparations) will be evaluated to identify changes in matrix composition consistent with osteochondrosis and to compare histological findings with (semi)quantitative MRI results. Synovial fluid and blood samples from goats with induced OC lesions will also be collected and evaluated to identify biomarkers of early OC lesions. The University of Minnesota is an ideal setting for the completion of the proposed research. The College of Veterinary Medicine provides the candidate access to state-of-the-art large and small animal surgical suites staffed with board certified surgeons, anesthesiologists and trained technical help. A 3T GE MRI scanner is also available on site for use. Dr. Carlson's laboratory is a well-developed resource for histological/morphological techniques, particularly in the area of bone and cartilage research. Close collaboration with the Center for Magnetic Resonance Research, an interdepartmental and interdisciplinary research laboratory, providing state-of-the-art instrumentation, expertise, and infrastructure enables the candidate to do basic and applied biomedical research using the unique capabilities provided by high field MRI. Finally, interaction with human orthopedic surgeons and researchers are enhanced by attendance at the Department of Orthopedic Surgery Grand Rounds held weekly.
Osteochondrosis is a developmental orthopedic disease that occurs secondary to a defect in vascular supply to growth cartilage in known predilection sites and is a common cause of degenerative joint disease later in life. In this project we will compare the vascular supply to growth cartilage at predilection and non-predilection sites of osteochondrosis in humans and animals. We then will develop an animal model of surgically induced osteochondrosis and use this model to perfect high field magnetic resonance imaging techniques to characterize the resulting changes in the cartilage and subchondral bone as the disease develops. Biomarkers to identify early subclinical disease and to distinguish healing vs. progressing lesions will also be investigated. The results of this work will allow: 1) a better understanding of the pathogenesis of osteochondrosis in humans; 2) diagnosis of the disease at an earlier stage than currently is possible; and 3) future development of improved medical and surgical treatments for this disease.
|Wang, Luning; Nissi, Mikko J; Toth, Ferenc et al. (2017) Quantitative susceptibility mapping detects abnormalities in cartilage canals in a goat model of preclinical osteochondritis dissecans. Magn Reson Med 77:1276-1283|
|Tóth, Ferenc; David, Frédéric H; LaFond, Elizabeth et al. (2017) In vivo visualization using MRI T2 mapping of induced osteochondrosis and osteochondritis dissecans lesions in goats undergoing controlled exercise. J Orthop Res 35:868-875|
|Tóth, Ferenc; Nissi, Mikko J; Ellermann, Jutta M et al. (2015) Novel Application of Magnetic Resonance Imaging Demonstrates Characteristic Differences in Vasculature at Predilection Sites of Osteochondritis Dissecans. Am J Sports Med 43:2522-7|
|Wang, Luning; Nissi, Mikko J; Tóth, Ferenc et al. (2015) Multiparametric MRI of Epiphyseal Cartilage Necrosis (Osteochondrosis) with Histological Validation in a Goat Model. PLoS One 10:e0140400|