Fig. 3
The calcaneus-cuboid-MTV (CCM) complex and cuneiform I are mechanosensitive sites. a, b Dorsolateral and plantar micro-CT views of hind paws of CIA in voluntary running mice. Black rectangle indicates CCM region, white ovals display sites of erosions. c Lateral micro-CT views of hind paws from TNF∆ARE voluntary running mice; eroded regions are encircled. d–f Microanatomy of dorsolateral, plantar and medial side of hind paws representing all tendons, ligaments, and muscles. CCM: black rectangle, Cuneiform I: grey rectangle. Indicated tendons in the CCM region are PL peroneus longus, PB peroneus brevis, AV abductor digiti V, CCL calcaneocuboid ligament, DL extensor digitorum lateralis, TA tibialis posterior, dl distal ligament, cl cuneosesamoid ligament, sml sesamoidalMT ligament. Functional enthesis ⌂, (e.g., sites where tendon wraps around a bone pulley and associated with a tendon sheath lined by a synovial membrane, rather than insertion in the immediate vicinity of these regions). g, h Bone erosion scores in CCM region in respectively CIA and TNF∆ARE mice under voluntary running or control conditions, n = 5; n = 7 each condition pooled data of two independent experiments, MWU, significance for CIA score range [2–4] and TNF∆ARE score range [2–3]. i Schematic view of hind paws divided into three regions: I (lateral), II (axial) and III (medial). H&E sections of all regions were generated and scored accordingly. 1-Talus (light pink) 2-Calcaneus (light grey) 3-Navicular bone (purple) 4-CuneiformI (blue) 5-Cuneiform II (blown) 6-Cuneiform III (yellow) 7-Cuboid bone (green) 8-Metatarsal V (orange) 9-Metatarsal IV 10- Fibula 11-Tibia and 12-13-14-Metatarsal I-II-III. j H&E section in voluntary running mice: early signs of inflammation in the CCM region. Scale bar: 0.2 mm. k H&E micro-inflammation scores at the lateral side (region I) of the mid foot increases upon biomechanical stress, KW and post-test, significance for CIA control vs. CIA unloaded and CIA voluntary running vs. CIA unloaded. l Incidence of local inflammation scores at the lateral side of the midfoot and hindfoot for three groups: CIA control (blue), CIA voluntary running (red) and CIA early diseased stage voluntary running. In all conditions inflammation occurs primary at the calcaneus/talus. Voluntary running increases inflammation at several sites, most pronounced at the CCM complex. Error bars show the mean ± s.e.m., if not mentioned otherwise data are representative for two independent experiments, *p < 0.05,**p < 0.01
