Time-dependent loss of mitochondrial function precedes progressive histologic cartilage degeneration in a rabbit meniscal destabilization model.
The goals of this work were to characterize progression of osteoarthritic cartilage degeneration in a rabbit medial meniscus destabilization (MMD) model and then to use the model to identify pre-histologic disruptions in chondrocyte metabolism under chronically elevated joint contact stresses in vivo. To characterize PTOA progression, 24 rabbits received either MMD or sham surgery. Limb loading was analyzed preoperatively and at regular postoperative intervals using a Tekscan pressure-sensitive walkway. Animals were euthanized 8 (n = 8 MMD; n = 8 sham) or 26 weeks (n = 8 MMD) postoperatively for histological cartilage evaluation by an objective, semi-automated Mankin scoring routine. To examine pre-histologic pathology, MMD was performed on an additional 20 rabbits, euthanized 1 (n = 9) or 4 weeks (n = 10) postoperatively. Chondrocytes were harvested fresh for measurement of mitochondrial function, an intracellular indicator of pathology after mechanical injury. Both MMD and sham surgery caused slight decreases in limb loading which returned to preoperative levels after 2 weeks. Histologically apparent cartilage damage progressed from 8 to 26 weeks after MMD. Changes in chondrocyte respiration were variable at 1 week, but by 4 weeks postoperatively chondrocyte mitochondrial function was significantly reduced. Many human injuries that lead to PTOA are relatively mild, and the cell-level mechanisms leading to disease remain unclear. We have documented PTOA progression in an animal model of subtle joint injury under continued use, and demonstrated that this model provides a realistic environment for investigation of multi-stage cellular pathology that develops prior to overt tissue degeneration and which could be targeted for disease modifying treatments. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:590-599, 2017.
Department of Orthopaedics and Rehabilitation, Orthopaedic Biomechanics Lab, University of Iowa, 2180 Westlawn Building, Iowa City, Iowa, 52242-110.|Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
Jessica E
JE
Goetz
Department of Orthopaedics and Rehabilitation, Orthopaedic Biomechanics Lab, University of Iowa, 2180 Westlawn Building, Iowa City, Iowa, 52242-110.
Mitchell C
MC
Coleman
Department of Orthopaedics and Rehabilitation, Orthopaedic Biomechanics Lab, University of Iowa, 2180 Westlawn Building, Iowa City, Iowa, 52242-110.
Douglas C
DC
Fredericks
Department of Orthopaedics and Rehabilitation, Orthopaedic Biomechanics Lab, University of Iowa, 2180 Westlawn Building, Iowa City, Iowa, 52242-110.
Emily
E
Petersen
Department of Orthopaedics and Rehabilitation, Orthopaedic Biomechanics Lab, University of Iowa, 2180 Westlawn Building, Iowa City, Iowa, 52242-110.|Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
James A
JA
Martin
Department of Orthopaedics, Indiana University Methodist Hospital, Indianapolis, Indiana.
Todd O
TO
McKinley
Department of Orthopaedics, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Saitama, Japan.
Yuki
Y
Tochigi
D000818:Animals; D019069:Cell Respiration; D019902:Chondrocytes / Q000378:metabolism*; D018450:Disease Progression; D008297:Male; D008592:Menisci, Tibial / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D010003:Osteoarthritis / Q000209:etiology* / Q000378:metabolism; D011817:Rabbits; D000070600:Tibial Meniscus Injuries / Q000150:complications* / Q000378:metabolism* / Q000473:pathology
Mankin score; mitochondria; overload; post-traumatic osteoarthritis; rabbit