Researchers identify key players in abnormal bone differentiation

The mutation blocks the normal development of bone stem cells into mature cells, which would form healthy bones. Instead, the mutation leads to the formation of extremely fragile bones. Children with this disorder experience recurrent fractures, bone deformities, chronic pain and other complications. The results, published in THE Journal of Clinical Investigationoffer new possibilities for designing therapies for this still incurable disease.

“Brittle bone diseases, also known as osteogenesis imperfecta (OI), are a group of rare diseases that affect connective tissue – tissues like bones, which support and protect other tissues in the body,” said Dr. Brendan Lee, Professor and Chairholder. and the Robert and Janice McNair Professor of Molecular and Human Genetics at Baylor. He is also a member of the Dan L Duncan Comprehensive Cancer Center at Baylor and is part of Texas Children's Hospital. “Most types of OI are caused by genetic mutations that disrupt collagen synthesis or processing, but not type V OI.”

“OI type V is unique because all patients have the exact same mutation in the IFITM5 gene linked to disease,” said the work’s first author, Dr. Ronit Marom, assistant professor of molecular and human genetics at Baylor and Texas Children’s. “This mutation results in the production of a longer IFITM5 protein; however, the biological function of this protein in bone and why this mutation results in OI were not well understood.

The researchers developed an animal model of type V OI by genetically modifying mice to express the mutant gene at certain stages of bone development. Genetically engineered mice have recapitulated most features of the human condition, allowing analysis of the underlying molecular mechanisms.

The team discovered that the IFITM5 the mutation acts at the level of bone stem cells, altering the normal process leading to bone formation. “Bone stem cells pave the way for skeleton formation during development and bone healing after fracture. They first give rise to cartilage, which then turns into bone,” Lee said.

THE Ifitm5 the mutation in mice disrupts this process. Instead of progressing from cartilage to bone, progenitor cells form overgrown cartilage calluses where new bone should be.

“Our findings help explain what we see in patients with OI type V. Not only do their bones break easily, but when stem cells try to heal them, they form large calluses of cartilage instead of bones,” Lee said. “It’s as if the stem cells don’t finish their work, they get stuck in a loop, preferably forming cartilage, instead of turning into bone.”

Until now, we considered OI to be the result of abnormal bone development. It was exciting to discover that type V OI is actually the result of abnormal differentiation of a common stem cell, leading to an imbalance in the development of cartilage and bone.

Dr. Ronit Marom, assistant professor, molecular and human genetics, Baylor College of Medicine

The team also identified two major molecular players at the origin of this bone maturation defect. “The ERK/MAP kinase signaling pathway and the SOX9 transcription factor were both significantly increased,” Marom said. “Interestingly, when we inactivated ERK/MAP kinase or SOX9 signaling with pharmacological or genetic approaches, we were able to restore normal bone development in mutant models. These findings not only inform the mechanism of type V OI, but will also facilitate normal bone development. development of future therapies for this condition.

“Additionally, the fact that all patients with OI type V present with the same IFITM5 “The mutation could prove to be an advantage for genetic therapies directed against the mutated gene,” Lee said. “A gene therapy designed to treat the mutated gene IFITM5 the mutation would work for all patients.

This study is another example of the value of rare disease studies in improving the understanding and treatment of common diseases. “Understanding how type V OI occurs provides new insights into similar but more common skeletal conditions, such as osteoporosis, and could also lead to better treatments,” Lee said.