The molecular role of site-2 protease for osteoblast function

• Applicant: Professorin Dr. Zoya Ignatova, since 4/2024
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 506621076

Osteogenesis imperfecta is a group of rare inherited bone dysplasias characterized by skeletal abnormalities, including bone fragility, short stature and various bone deformities in affected individuals. The most common ‘classic’ types of osteogenesis imperfecta are caused by mutations in two genes encoding the polypeptide chains of collagen type I, the most abundant extracellular matrix protein secreted by osteoblasts in the bone. The only X-linked recessive form of osteogenesis imperfecta identified so far has been shown to be associated with mutations in the MBTPS2 gene, encoding the site-2 protease (S2P). S2P is a Golgi-resident membrane protease that activates a number of membrane-bound transcription factors involved in lipid metabolism and response to endoplasmic reticulum (ER) stress. Since collagen-producing osteoblasts exhibit high protein synthesis rates, even modest deficits in the ER stress response and proteostasis can compromise their differentiation, collagen deposition and, eventually, bone tissue homeostasis. Whether an impaired ER stress response, lipid dysregulation and/or other yet unknown factors underlie the pathomechanism of the MBTPS2-linked form of osteogenesis imperfecta remains to be determined. Because several transcription factors are processed by S2P, the effect of S2P deficiency on the skeletal tissue is likely to be multifactorial. Therefore, the primary goal of this project is to reveal the mechanisms that implicate the S2P protease in the regulation of bone tissue maintenance by using an osteoblast-based model of MBTPS2-linked osteogenesis imperfecta. Pursuing this aim, we will perform transcriptomic and proteomic profilings of S2P-deficient osteoblasts to identify molecular pathways and factors that are specifically affected by the lack of S2P during osteoblast differentiation in vitro. We will also investigate the role of the two subbranches of ATF6 signaling, which are proteolytically activated by S2P upon ER stress and whose specific downstream target genes with regard to osteoblast function have been poorly studied thus far. Whether the ATF6α and/or ATF6β signaling pathway is critical for osteoblast differentiation and collagen synthesis will be addressed using stably expressing cell lines. Finally, we aim to identify whether S2P-deficient osteoblasts endure deregulated proteostasis and which molecular determinants may serve as potential therapeutic targets to rescue the phenotype of S2P-deficient bone cells.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Dr. Tatyana Danyukova, until 3/2024