Background/Purpose: Osteoarthritis (OA) is a biomechanical joint disease mainly affecting articular cartilage and subchondral bone. A great variety of animal models, especially mice, are used trying to mimic human disease and its pathogenesis. Unlike in humans, mouse growth plates (GP) do not completely fuse and disappear. GP chondrocytes arrange in columns, where Hedgehog (Hh) pathway plays a key role orchestrating chondrocyte differentiation. In fact, we have previously shown that Evc^-/- mouse embryos exhibit loss of columns in the GP, premature hypertrophy and shorter bones due to the disruption of the Hh pathway. In neonatal mice, an altered mechanical joint loading due to hemiplegia induces disorganization of chondrocyte columns in the GP. However, it is unclear whether joint biomechanical alteration modifies GP structure in adult mice. Our aim was to study whether OA can disturb GP organization in adult mice and to assess whether the GP alteration may have an additional deleterious effect on the articular cartilage damage.

Methods: Knee OA was induced by medial meniscus sectioning in wild-type (WT) adult mice and let evolve for 8 weeks. We used an Evc tamoxifen (Tx) induced conditional knock out (cKO) model to achieve intermediate (Evc^cKO+/-, +Vehicle) or null (Evc^cKO-/-, +Tx) Evc levels in adult mice, as a control for GP disorganization. Mice were randomly assigned to different groups: healthy WT (n=8), OA WT (n=6), healthy Evc^cKO+/- (n=4), OA Evc^cKO+/- (n=5), healthy Evc^cKO-/- (n=3) and OA Evc^cKO-/- (n=6). GP organization assessment was performed at the central region of the tibia, and expressed as Column Index (CI). CI was calculated as the percentage of GP chondrocytes in columns, with at least 3 cells less than 20 pixels apart, angles ranging from 155° to 180°, and corrected by column length¹. Articular cartilage damage was evaluated by OARSI score and GP thickness measured in Safranin-O stained sections.

Results: GP column measurements revealed that CI decreased by 50% in OA WT mice, showing altered columnar structure and clusters of cells (Healthy WT: 2225±125; OA WT: 682±69; p=0.0001). Healthy Evc^cKO+/- mice exhibited a low CI (1015±130; p=0.0004 vs Healthy WT) while a complete Evc deletion showed a significant loss of GP organization (Healthy Evc^cKO-/-: 462±76; p=0.005 vs Healthy Evc^cKO+/-). In Evc^cKO-/- mice, OA drastically reduced CI (229±55; p=0.0002 vs OA WT). No changes were observed regarding GP thickness or proteoglycan content between groups. Neither a partial deletion nor a complete loss of Evc induced cartilage damage in mice (p=0.73 and 0.11 vs Healthy WT respectively). In addition, OA WT and OA Evc^cKO-/- mice showed equally severe lesions in the articular cartilage (p=0.64).

Conclusion: Profound GP chondrocyte disorganization occurred in OA adult mice due to joint instability. However, the altered GP column structure in Evc^cKO/- mice did not exacerbate articular cartilage damage. Although OA leads to the loss of GP chondrocyte column structure, this alteration in the GP does not seem to void mouse experimental models of OA. Further studies are needed to confirm the lack of interference of GP pathological state on articular cartilage damage in mouse OA.

¹ Killion CH et al. Mol Biol Cell. 2017 Jul 7;28(14):1862-1870

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/disorganization-of-chondrocyte-columns-in-the-growth-plate-during-experimental-osteoarthritis-in-mice/