Do 3D epiphyseal bone architectural changes in ageing STR/ Ort and healthy mice reveal early imaging biomarkers of osteoarthritis?

Novel imaging biomarkers are required to advance research into,and treatment of, knee joint osteoarthritis (OA). Currently,early-stage OA is undetectable in humans, and treatment effec-tiveness cannot be reliably monitored. STR/Ort mice are anage-related model of progressive OA, in which predisposition(at 10 weeks of age), early-stage onset (at 20 weeks), and late-stage OA (at 40 weeks) are well-defined. Using STR/Ort(OA) and CBA (healthy parental control) mice at these age inter-vals, knee joints were non-invasivelyμCT-imaged with effectivepixel size 5μm. Tibial epiphyses were semi-automatically seg-mented from joints and separated into their constituent anatom-ical components: cortical bone, trabecular bone, and marrowspace volume (Fig. 1A–D). Crucially, these bony features can bedetected in human knees using clinical in vivo scanners(XtremeCT II HR-pQCT, Scanco Medical) making translation ofour research realistically attainable in the near-future.3D analyses of tibial epiphyses followed by two-way ANOVA con-firmed significant age- and/or strain-related differences in epiph-yseal cortical bone volume (p≤0.001), trabecular bone volume(p≤0.001), mean trabecular and cortical bone thicknesses (bothpvalues≤0.010), trabecular volume relative to cortical volume(p≤0.001), and degree of anisotropy, a descriptive measure-ment of trabecular orientation (p=0.001, Fig. 1E). The twomouse strains had different epiphyseal growth patternsthroughout life with respect to total epiphyseal volume(p=0.023), marrow space volume (p=0.002), and trabecularvolume relative to epiphyseal interior volume (p=0.024), as wellas changes in trabecular anisotropy indicating divergent and identified in a HBM pedigree, which was independently con-firmed in two unrelated HBM cases. SMAD9 is an inhibiting tran-scription factor in the bone morphogenetic protein (BMP)signaling pathway, whereas SMAD1/5 activate transcription.Zebrafish are a suitable model as they have similar skeletal phys-iology to humans and can be easily pharmacologically manipu-lated and imaged