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Updated: May 29, 2025
Imaging Denatured Collagen Strands In vivo and Ex vivo via Photo-triggered Hybridization of Caged Collagen Mimetic Peptides
Published on: January 31, 2014
The administration of exogenous HSP47 as a collagen-specific therapeutic approach
Roberta Besio1, Nadia Garibaldi1, Alessandra Sala1
1Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy.
Abstract:
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.
Insights
Heat shock protein 47 (HSP47) shows therapeutic potential for osteogenesis imperfecta (OI) by improving collagen I processing. Treatment with recombinant HSP47 (rHSP47) enhanced collagen secretion and bone mineralization in OI models.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Osteogenesis imperfecta (OI) is a collagen disorder caused by mutations affecting collagen I synthesis and processing.
- OI mutations often lead to delayed collagen folding, aberrant posttranslational modifications, and impaired extracellular matrix assembly.
- Primary fibroblasts from OI individuals with defects in the collagen prolyl 3-hydroxylation complex exhibit homogeneous collagen overmodification.
Purpose of the Study:
- To demonstrate the therapeutic potential of heat shock protein 47 (HSP47) for osteogenesis imperfecta (OI).
- To investigate the effects of exogenous recombinant HSP47 (rHSP47) on collagen I processing and cellular homeostasis in OI models.
- To evaluate the in vivo efficacy of rHSP47 in a zebrafish OI model.
Main Methods:
- Utilized primary fibroblasts from OI individuals with specific collagen prolyl 3-hydroxylation complex defects.
- Administered exogenous recombinant HSP47 (rHSP47) to OI fibroblasts and analyzed its cellular localization.
- Assessed collagen secretion, posttranslational modifications, intracellular collagen retention, and ER proteostasis.
- Investigated mutation-dependent effects of rHSP47 in fibroblasts from different OI probands.
- Evaluated bone mineralization in vivo using the zebrafish p3h1-/- OI model.
Main Results:
- Exogenous rHSP47 was effectively taken up by OI cells and localized to ER exit sites and the ER-Golgi intermediate compartment.
- rHSP47 treatment significantly increased collagen secretion and reduced collagen posttranslational modifications and intracellular retention.
- General ER proteostasis, cellular homeostasis, and vitality were ameliorated by rHSP47.
- Increased collagen content was observed in the extracellular matrix of treated OI cells.
- rHSP47 demonstrated mutation-dependent efficacy, being effective only in cells with the most N-terminal defects.
- A beneficial effect on bone mineralization was observed in the zebrafish p3h1-/- OI model.
Conclusions:
- Recombinant HSP47 (rHSP47) effectively improves collagen I processing and cellular homeostasis in osteogenesis imperfecta (OI) models.
- rHSP47 shows promise as a therapeutic agent for OI by enhancing collagen secretion and matrix quality.
- The study highlights the potential of targeting protein folding and quality control mechanisms for treating collagenopathies.
- rHSP47's efficacy is dependent on the specific collagen mutation, suggesting personalized therapeutic approaches may be necessary.
- In vivo studies in zebrafish confirm the potential of rHSP47 to improve bone mineralization in OI.
