The administration of exogenous HSP47 as a collagen-specific therapeutic approach.

The proof of principle of the therapeutic potential of heat shock protein 47 (HSP47) for diseases characterized by defects in collagen I synthesis is here demonstrated in osteogenesis imperfecta (OI), a prototype of collagen disorders. Most of the OI mutations delay collagen I chain folding, increasing their exposure to posttranslational modifications that affect collagen secretion and impact extracellular matrix fibril assembly. As a model, we used primary fibroblasts from OI individuals with a defect in the collagen prolyl 3-hydroxylation complex, since they are characterized by the synthesis of homogeneously overmodified collagen molecules. We demonstrated that exogenous recombinant HSP47 (rHSP47) is taken up by the cells and localizes at the ER exit sites and ER-Golgi intermediate compartment. rHSP47 treatment increased collagen secretion, reduced collagen posttranslational modifications and intracellular collagen retention, and ameliorated general ER proteostasis, leading to improved cellular homeostasis and vitality. These positive changes were also mirrored by an increased collagen content in the OI matrix. A mutation-dependent effect was found in fibroblasts from 3 probands with collagen I mutations, for which rHSP47 was effective only in cells with the most N-terminal defect. A beneficial effect on bone mineralization was demonstrated in vivo in the zebrafish p3h1-/- OI model.