Progressive cell‐mediated changes in articular cartilage and bone in mice are initiated by a single session of controlled cyclic compressive loading

Abstract

We previously showed that repetitive cyclic loading of the mouse knee joint causes changes that recapitulate the features of osteoarthritis (OA) in humans. By applying a single loading session, we characterized the temporal progression of the structural and compositional changes in subchondral bone and articular cartilage. We applied loading during a single 5-minute session to the left tibia of adult (26-week-old) C57Bl/6 male mice at a peak load of 9.0N for 1200 cycles. Knee joints were collected at times 0, 1, and 2 weeks after loading. The changes in articular cartilage and subchondral bone were analyzed by histology, immunohistochemistry (caspase-3 and cathepsin K), and microcomputed tomography. At time 0, no change was evident in chondrocyte viability or cartilage or subchondral bone integrity. However, cartilage pathology demonstrated by localized thinning and proteoglycan loss occurred at 1 and 2 weeks after the single session of loading. Transient cancellous bone loss was evident at 1 week, associated with increased osteoclast number. Bone loss was reversed to control levels at 2 weeks. We observed formation of fibrous and cartilaginous tissues at the joint margins at 1 and 2 weeks. Our findings demonstrate that a single session of noninvasive loading leads to the development of OA-like morphological and cellular alterations in articular cartilage and subchondral bone. The loss in subchondral trabecular bone mass and thickness returns to control levels at 2 weeks, whereas the cartilage thinning and proteoglycan loss persist.

Role of subchondral bone properties and changes in development of load-induced osteoarthritis in mice

“…Using a peak load of 9N for 1200 cycles, this model induced controlled instabilities in the knee joint 31 , and recapitulated OA pathology in the cartilage and SCB after 1, 2, and 6 weeks of daily loading in adult C57BL/6 mice 27,28 . A single bout of loading also induced disease initiation and progression, demonstrating that OA pathology in this model can be initiated by cell-mediated processes that are activated by mechanical loading 32 .…”

“…Loading initially decreased cancellous TMD in both ALN- and VEH-treated groups; however, cancellous TMD was maintained without further loss thereafter with ALN treatment. Differences in these data compared to results obtained in post-traumatic injury models of OA may reflect the non-invasive nature of our model compared to the surgical intervention required in other models 32 . In this study, ALN generally did not inhibit load-induced changes in bone and had differential effects on cartilage changes depending on mouse strain.…”

“…Cartilage degradation was examined by a blinded observer using a modified murine cartilage histological scoring system 37 on the most posterior 180μm of the tibial plateau. Scores from the posterior medial and lateral plateaus were summed for our analyses, as these regions exhibited the most cartilage damage in previous studies 27,32 .…”

Collagen XI mutation lowers susceptibility to load‐induced cartilage damage in mice

“…Structural cartilage damage after loading was evaluated in all limbs using the OARSI scoring system . Cartilage thickness was measured in both the medial and lateral plateaus on three representative sections in the joint (posterior, middle, and anterior) as described previously …”

“…We also assessed chondrocyte apoptosis using a TUNEL kit to detect DNA strand breaks (Sigma, 11684795910 Roche, Darmstadt, Germany). We analyzed the medial posterior tibial plateau at early time points under high loads, because the majority of load‐induced damage occurs in this region, and a single session of 9 N cyclic compression leads to progressive cell‐mediated changes and cartilage degradation at 1 and 2 weeks …”