Delayed Bone Fracture Healing in Hybid (Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization)-Deficient...

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), essential for HA degradation, has been reported to promote endochondral ossification in developing bone but to inhibit intramembranous ossification. However, little is known about the role of HYBID in long bone fracture healing, which requires both types of ossification. The role of genetic Hybid depletion in healing was examined in a murine model of femoral diaphyseal fracture. On micro-computed tomography, bridging of fracture gaps was delayed in Hybid-deficient (Hybid^-/-) mice compared to wild-type mice. On histologic analysis, the resorption of cartilaginous callus was retarded due to decreased osteoclasts/chondroclasts and blood vessels at the chondro-osseous junction of cartilaginous and bony callus in Hybid deficiency, with delayed fusion of fracture gaps. At 2 weeks after fracture, Hybid was highly expressed by osteoblasts and hypertrophic chondrocytes in callus of wild-type mice, and Il6 was overexpressed at 1 week, followed by transforming growth factor β1 (Tgfb1) and bone morphogenic protein 2 (Bmp2) expression at 2 and 3 weeks. High-molecular-weight HA accumulated in the callus tissue of the Hybid^-/- mice. In both groups, fracture healing was promoted with injections of low-molecular-weight HA around the calluses of the fractured femora. These data suggest that fracture healing is delayed in HYBID deficiency due to impaired endochondral ossification, and that HYBID-mediated HA depolymerization is involved in bone fracture healing.