Topographic modeling of early human osteoarthritis in sheep

Abstract

Articular cartilage damage occurring during early osteoarthritis (OA) is a key event marking the development of the disease. Here, we modeled early human OA by gathering detailed spatiotemporal data from surgically induced knee OA development in sheep. We identified a specific topographical pattern of osteochondral changes instructed by a defined meniscal injury, showing that both cartilage and subchondral bone degeneration are initiated from the region adjacent to the damage. Alterations of the subarticular spongiosa arising locally and progressing globally disturbed the correlations of cartilage with subchondral bone seen at homeostasis and were indicative of disease progression. We validated our quantitative findings against human OA, showing a similar pattern of early OA correlating with regions of meniscal loss and an analogous late critical disturbance within the entire osteochondral unit. This translational model system can be used to elucidate mechanisms of OA development and provides a roadmap for investigating regenerative therapies.

Transection of the medial meniscus anterior horn results in cartilage degeneration and meniscus remodeling in a large animal model

“…Our findings are also consistent with a longer term (6 months) porcine and ovine models that showed severe degeneration of the cartilage surfaces after an open en bloc removal of a segment of the anterior horn of the medial meniscus 25,26 . In addition, our findings are in agreement with a canine study in which an arthroscopic posterior medial meniscal release resulted in increased OA histologic scoring and slight subchondral sclerosis 28 .…”

“…This is particularly important given our findings that cartilage wear initially occurred within the cartilage‐meniscus contact region of the medial compartment rather than across the condyle as a whole. This spatial difference is in agreement with another large animal model of meniscal injury 26 . In addition, larger animals make possible the use of arthroscopic injury and repair approaches 51 .…”

“…Of particular note, Waller et al 25 developed an excisional model in the anterior horn of the Yucatan minipig using an open approach and showed marked degradation of the joint cartilage at 6 months. In a similar anterior horn excision procedure in sheep, Oláh et al 26 also saw marked degeneration at both 6 weeks and 6 months post injury. In a canine model, Luther et al developed an arthroscopic approach to bisect the posterior medial meniscus, creating a meniscal release injury model.…”

“…While most agree that large animal models are a necessary next step in translation, there is not yet consensus on which large animal is a gold standard for meniscus research, 22 with each model having some strengths and weaknesses 23 . Indeed, a number of large animal meniscus injury/joint degeneration models have been developed across a range of species 24‐27 . Of particular note, Waller et al 25 developed an excisional model in the anterior horn of the Yucatan minipig using an open approach and showed marked degradation of the joint cartilage at 6 months.…”

A novel cryo-embedding method for in-depth analysis of craniofacial mini pig bone specimens

“…The high costs associated with purchase and housing of large animals, along with the duration of the study, are critical factors in this regard 41 . This is especially relevant when evaluating clinical conditions that are slowly progressive/ degenerative in nature 42 ; such studies are often cost-prohibitive in large animals. The cryo-processing methods shown here are readily adaptable to tissues from human subjects and other large animal models, on par with that typically found in rodent studies.…”