Interview with Ronit Marom,MD PhD and Assistant Professor at
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

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Interview with Ronit Marom, MD PhD and Assistant Professor at Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

Who are you & what is your relationship to OI?

I am a pediatrician and a geneticist with a special interest in genetic bone fragility. I completed my M.D./Ph.D. degree in Tel Aviv University in Israel, where I worked in the lab of Dr. Dafna Benayahu who is studying skeletal stem cells and their fate in the bone marrow microenvironment. I completed my Pediatrics residency in Tel Aviv Medical Center, and my clinical training in Medical Genetics and Medical Biochemical Genetics at Baylor College of Medicine in Houston, Texas.

In 2012 I joined the lab of Dr. Brendan Lee, whose pioneering work has driven many discoveries in the field of skeletal dysplasias and particularly in osteogenesis imperfecta (OI). As a postdoctoral fellow in the Lee lab, we investigated the mechanism of OI type V and worked on other gene discovery projects focused on inherited bone fragility.

With Dr. Lee’s mentorship, I learned how insights from basic science studies can be translated to advance diagnosis and treatment in the patients.

In 2016 I became a fellow of the OI Foundation and had the exceptional opportunity to interact with other researchers in the field, and meet the patients and families, from whom I learned first-hand about the experiences and challenges of individuals affected with OI. The genetic etiology and mechanisms of bone fragility continue to be the focus of my research mission that I now pursue as a physician-scientist in my lab at Baylor College of Medicine.

Tell us about the project about molecular events leading to osteogenesis imperfecta type V

The goal of this project was to understand how OI type V, a rare form of OI that is not associated with a collagen defect, disrupts skeletal development. OI type V is unique because all patients have the exact same mutation (or pathogenic variant) in IFITM5 gene. This mutation results in a longer IFITM5 protein. However, the biological function of this protein in bone and why this mutation results in OI were not well understood. Previous mouse models (published by us and others) did not survive long enough to study the effect of this mutation on the growing skeleton. We have generated a viable mouse model for OI type V by activating the expression of the IFITM5 mutation during certain stages in bone and cartilage development.

We found that skeletal stem cells expressing the mutant IFITM5 protein in our mouse model are “shifting directions” early in development to form cartilage where there should be new bone formation instead. This resulted in cartilage overgrowth and short, weak bones that are not mineralized well, similar to what is seen in patients with OI type V.

We also found two major players contributing to this phenotype: The ERK/MAP kinase signalling pathway and the transcription factor SOX9 were both significantly increased. Interestingly, when we inactivated either ERK/MAP kinase signalling or SOX9 (by using pharmacologic or genetic approaches), we were able to restore the normal bone development in the mutant mice. The work was supported by the OI Foundation, the Lawrence Family Bone Disease Program of Texas, the Chao Foundation at Baylor College of Medicine, the Brittle Bone Disorders Consortium (BBDC) and the National Institutes of Health as research grants to the group of Brendan Lee and collaborating investigators.

For those who are not familiar with OI type 5, Is it only a genetic type or would you say that OI type 5 is also a clinical type? What characterizes it? How is it different from OI caused by COL genes?

OI type V was first described as a clinical type by the group of Dr. Francis Glorieux and colleagues. They distinguished it from other forms of OI by its unique clinical features, including the formation of large (hyperplastic) callus that usually develops after fractures or surgeries, and the calcification of the interosseous membranes connecting the bones of the forearms and legs. In 2012 a few groups reported a recurrent mutation in IFITM5 gene as the genetic cause of OI type V. The mutation is inherited in an autosomal-dominant manner. Individuals with OI type V have moderate bone fragility. Interestingly, although all patients have the same mutation, the clinical severity can be variable (even between members of the same family).

What were your most interesting findings?

The first interesting finding from this study is that OI type V is in fact an osteochondrodysplasia, meaning that it is caused by imbalance in both cartilage and bone formation, due to abnormal maturation of a common skeletal stem cell. The signalling defect via ERK-SOX9 activation is an exciting finding, because it teaches us on the mechanism of OI type V and may be targeted for future therapies for this condition. Lastly, we showed that the mouse model has similar skeletal abnormalities compared to the human patients and therefore can be used as a pre-clinical model to further study OI type V.

Were patients/patient organizations involved, and how?

Our long-term partnership with the OI Foundation and the Brittle Bone Disorders Consortium (BBDC) of the Rare Diseases Clinical Research Network (RDCRN) was instrumental to the study. I am also thankful to all the patients and families that I have met and that inspired me to pursue my research work.

How can we improve the collaboration between basic scientists and clinicians?

Our study on OI type V is the result of collaborative work between physician-scientists, basic scientists and clinicians. These types of interactions are critical to advance our knowledge, especially in the field of rare diseases. Scientific conferences provide us with the opportunity to meet, interact and collaborate based on mutual research interests. I also try to attend at least some of the online webinars, workshops and virtual meetings (such as those organized by the OIFE) as they expand my exposure to experts and discoveries from around the globe.

In your opinion – what are the biggest knowledge gaps in OI research?

Our knowledge has advanced in terms of the genetic basis of OI, but the clinical challenges still exist and there is an unmet need for better therapies for OI. There are more than 20 genes that are associated with OI, but despite this genetic diversity we think that different types of OI may share similar mechanisms leading to bone fragility in the patients. We need to gain better understanding of these mechanisms, and then translate this knowledge to developing therapies.

Any messages for the readers of OIFE Magazine?

We should continue to work together – patients and families, medical providers and scientists – to achieve the common goal of improving the understanding, management and outcome of brittle bone diseases.