The molecular chaperone Hsp47 is essential for cartilage and endochondral bone formation

Abstract

Heat shock protein 47 kDa (Hsp47) is considered as a molecular chaperone essential for the correct folding of type I and type IV procollagen in the ER. However, the function of Hsp47 for other types of procollagen and its importance for chondrogenesis have never been elucidated. To examine the function of Hsp47 in cartilage formation and endochondral ossification, we conditionally inactivated the Hsp47 gene in chondrocytes using Hsp47 floxed mice and mice carrying a chondrocyte-specific Col2a1–Cre transgene. Hsp47 conditional null mutant mice died just before or shortly after birth, and exhibited severe generalized chondrodysplasia and bone deformities with lower levels of type II and type XI collagen. Second-harmonic generation (SHG) analysis and electron microscopy revealed the accumulation of misaligned type I collagen molecules in the intervertebral discs and a substantial decrease in type II collagen fibers, respectively. Whole-mount skeletal staining showed no calcified region in the vertebral bodies of sacral vertebrae, and revealed that the endochondral bones were severely twisted and shortened. These results demonstrate that Hsp47 is indispensable for well-organized cartilage and normal endochondral bone formation.