Diastrophic dysplasia (DTD) is an incurable recessive chondrodysplasia caused by mutations in the SLC26A2 transporter responsible for
sulfate uptake by chondrocytes. The mutations cause undersulfation of
glycosaminoglycans in cartilage. Studies of dtd mice with a knock-in Slc26a2 mutation showed an unusual progression of the disorder: net undersulfation is mild and normalizing with age, but the articular cartilage degrades with age and bones develop abnormally. To understand underlying mechanisms, we studied newborn dtd mice. We developed, verified and used high-definition infrared hyperspectral imaging of cartilage sections at physiological conditions, to quantify
collagen and its orientation, noncollagenous
proteins, and
chondroitin chains, and their sulfation with 6-μm spatial resolution and without labeling. We found that
chondroitin sulfation across the proximal femur cartilage varied dramatically in dtd, but not in the wild type. Corresponding undersulfation of dtd was mild in most regions, but strong in narrow articular and growth plate regions crucial for bone development. This undersulfation correlated with the
chondroitin synthesis rate measured via radioactive
sulfate incorporation, explaining the sulfation normalization with age.
Collagen orientation was reduced, and the reduction correlated with
chondroitin undersulfation. Such disorientation involved the layer of
collagen covering the articular surface and protecting cartilage from degradation. Malformation of this layer may contribute to the degradation progression with age and to
collagen and
proteoglycan depletion from the articular region, which we observed in mice already at birth. The results provide clues to in vivo sulfation, DTD treatment, and cartilage growth.