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. 2019 Aug 1;218(9):3134–3152. doi: 10.1083/jcb.201906059

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© 2019 Saw et al.

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Figure 5. — Metalloprotease-resistant aggrecan rescues long bone proportionality. (A) Structure of aggrecan and the Chloe/Jaffa knock-in mutation. The aggrecan protein core (gray) contains three globular regions (G1–G3) and has ∼100 glycosaminoglycan chains (purple) attached. MMP and ADAMTS cleavage sites are indicated by black arrows. Disruption of specific cleavage sites by knock-in mutations are indicated by an x. Schematic of breeding strategies to generate J-QT3^+/− and C-QT3^+/− mice. CS1, chondroitin sulfate domain 1; CS2, chondroitin sulfate domain 2; KS, keratan sulfate. (B) Representative micro-CT images used to measure the length of sternum, the spine, and the leg bones of 8-wk old WT, QT3^+/−, C-QT3^+/−, and J-QT3^+/−. Sternum (upper panel), spine (middle panel), and leg bones (lower panel). Arrows indicate measurements as described in legend of Fig. 1 H. (C) Quantification of axial and appendicular bones length in 8-wk-old WT, QT3^+/−, C-QT3^+/−, and J-QT3^+/−. The sternum, spine, femur, and tibia are all shorter in the QT3^+/− mouse compared with WT controls (dashed lines: WT, orange; QT3^+/−, gray). C-QT3^+/− mice have shorter sternums. Sternum:thoracic spine ratio indicates the effect was more pronounced in sternum than spine. C-QT3^+/− partially rescued the shortened QT3^+/− femur length, but J-QT3^+/− mice could not. The femur:tibia ratio reflects that C-QT3^+/− mice partially restored the leg bone compared with QT3^+/− (n = 5–7/each group). Mean values of each dataset are plotted in graphs with error bars representing SEM. Datasets were compared by unpaired t test, *, P < 0.05; ****, P < 0.0001. Dunnett’s test P < 0.05 when WT or QT3^+/− compared with C-QT3^+/− (blue*) or J-QT3^+/− (pink*). (D) Safranin O–stained knee joints of WT, QT3^+/−, C-QT3^+/−, and J-QT3^+/− mice at 8 wk of age. Black arrows show growth plate closure in femur and tibia of QT3^+/− mice; femur growth plate is rescued in the C-QT3^+/− but not in J-QT3^+/−, while the tibia growth plate is rescued by both mutant aggrecan (4×/0.5-NA objective). (E) H&E-stained femur and tibia growth plates of WT, QT3^+/−, C-QT3^+/−, and J-QT3^+/− mice (8-wk-old) chondrocyte disorganization in the growth plates of QT3^+/− femur and tibia, J-QT3^+/− femur but not in the C-QT3^+/− mice. Scale bar = 50 µm; 20×/0.5-NA objective.