Osteoarthritis results from the degradation of articular cartilage and is one of the leading global causes of pain and immobility. Cartilage has a limited capacity for self-repair. While repair can be enhanced through surgical intervention, current methods often generate inferior fibrocartilage and repair is transient. The development of tissue engineering strategies to improve repair outcomes is an active area of research. While small animal models such as rodents and rabbits are often used in early pre-clinical work, larger animals that better recapitulate the anatomy and loading of the human joint are required for late-stage preclinical evaluation. Because of their physiological similarities to humans, and low cost relative to other large animals, sheep are routinely used in orthopedic research, including cartilage repair studies. In recent years, there has been considerable research investment into the development of cartilage repair strategies that utilize mesenchymal stem/stromal cells (MSC). In contrast to autologous chondrocytes derived from biopsies of articular cartilage, MSC offer some benefits including greater expansion capacity and elimination of the risk of morbidity at the cartilage biopsy site. The disadvantages of MSC are related to the challenges of inducing and maintaining a stable chondrocyte-like cell population capable of generating hyaline cartilage. Ovine MSC (oMSC) biology and their utility in sheep cartilage repair models have not been reviewed. Herein, we review the biological properties of MSC derived from sheep tissues, and the use of these cells to study articular cartilage repair in this large animal model.

A previous study identified kartogenin (KGN) as a potent modulator of bone marrow mesenchymal stem/stromal cell (BMSC) chondrogenesis. This initial report did not contrast KGN directly against transforming growth factor-beta 1 (TGF-β1), the most common growth factor used in chondrogenic induction medium. Herein, we directly compared the in vitro chondrogenic potency of TGF-β1 and KGN using a high resolution micropellet model system. Micropellets were cultured for 7-14 days in medium supplemented with TGF-β1, KGN, or both TGF-β1 + KGN. Following 14 days of induction, micropellets exposed to TGF-β1 alone or TGF-β1 + KGN in combination were larger and produced more glycosominoglycan (GAG) than KGN-only cultures. When TGF-β1 + KGN was used, GAG quantities were similar or slightly greater than the TGF-β1-only cultures, depending on the BMSC donor. BMSC micropellet cultures supplemented with KGN alone contracted in size over the culture period and produced minimal GAG. Indicators of hypertrophy were not mitigated in TGF-β1 + KGN cultures, suggesting that KGN does not obstruct BMSC hypertrophy. KGN appears to have weak chondrogenic potency in human BMSC cultures relative to TGF-β1, does not obstruct hypertrophy, and may not be a viable alternative to growth factors in cartilage tissue engineering. Cartilage has a limited capacity for self-repair, and focal defects have a propensity to degrade further, resulting in osteoarthritis (OA). OA is the leading cause of pain and disability in the western world 1. Considerable research investment is being made towards the development of strategies for cell-based cartilage repair. Bone marrow-derived mesenchymal stem/stromal cells (BMSC) are thought to be a promising cell population for use in cartilage defect repair 2. To induce BMSC chondrogenic differentiation, culture medium is traditionally supplemented with a variety of molecules said to be "chondrogenic". While many pro-chondrogenic compounds have been extensively reported and used in differentiation assays 3,4 , laboratory-generated cartilage tissue does not yet yield structural and functional properties equivalent to native cartilage 2. Kartogenin (KGN), a small heterocyclic non-protein compound, was identified from a screen of 22,000 compounds as the most promising small molecule for inducing BMSC chondrogenesis 5. While the initial report was promising, human BMSC response to KGN was not contrasted against more commonly used

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