Restoring the Wnt/β-catenin signaling rescues bone defects in Job syndrome

Dr. Prem Swaroop Yadav was born in the Chaubeypur village of Varanasi district of Uttar Pradesh, India. He finished his schooling from the Govt. Queens Inter College (GIC), Varanasi. After completing his Bachelor’s and Master’s degrees from the Udai Pratap Autonomous College in Varanasi, he joined the PhD program at the Biological Sciences and Bioengineering (BSBE) Department, IIT Kanpur, India in 2016. He pursued his PhD under the supervision of Prof. Amitabha Bandyopadhyay. For his post-doctoral research, he moved to Boston, USA and joined the laboratory of Prof. Yingzi Yang at the Harvard School of Dental Medicine (HSDM) where he studied the pathophysiology of skeleton-related genetic disorders. Recently, he has joined Prof. Marie B. Demay’s group as a Research Fellow in Medicine at the Massachusetts General Hospital (MGH) & Harvard Medical School (HMS), Boston, USA. In Demay’s lab, he is investigating the role of key signaling pathways involved in hypertrophic differentiation of chondrocytes (which are the cartilage forming cells) and their endocrine regulation during bone development.

How would you explain your paper’s key results to the non-scientific community?

Job syndrome is a rare genetic disorder caused by mutations in STAT3 gene, largely manifested at a young age. The disease is primarily characterized by immune dysfunction and comorbid skeleton developmental abnormalities, including osteopenia, recurrent fracture of long bones, and scoliosis. One of the key characteristics of this disease is an elevated level of Immunoglobulin-E in the serum; therefore, it is also referred as Hyper Immunoglobulin-E Syndrome (HIES). So far, there is no targeted cure for this disease, and only symptomatic treatments are available. To understand the cellular and molecular mechanisms underlying the skeleton defects observed in Job syndrome, we genetically deleted the Stat3 gene in osteoprogenitor cells (stem cells for cartilage & bone) in mice. Using different experimental approaches, we demonstrated that the Stat3 function is essential in osteoblast lineage cells for the proper development of osteoblasts, the bone-forming cell types. Stat3 was found to be required for maintaining Wnt/β-catenin signaling, a key signaling pathway necessary for normal bone development. We have shown that ablation of Stat3 impaired the normal bone formation due to reduced Wnt/β-catenin signaling with an increase in Sclerostin (Sost) protein, an inhibitor of Wnt/ β-catenin signaling. Our research provides a foundation for further investigation on the principles whereby Stat3 regulates the non-immune cells and governs bone formation and maintenance. Furthermore, we also demonstrated that restoration of Wnt/β-catenin signaling using BIO, a small molecule inhibitor of GSK3, or genetically using Lrp5 gain of function (GOF) allele, rescued the skeletal defects cause by Stat3 loss to a large extent. Overall, our results strongly suggest that enhancing Wnt/β-catenin signaling could be a potential therapeutic approach to reduce bone defects in Job syndrome patients.

Graphical summary

What are the possible consequences of these findings for your research area?

Studying the underlying cellular and molecular mechanisms of rare genetic diseases provides invaluable insights into human biology and the pathophysiology of rare genetic disorders. The results from our work provide a basic understanding of why patients with Job syndrome have skeletal abnormalities and what is the molecular mechanism behind these defects. Our study and future research would help us develop better therapeutics for treating Job syndrome patients.

What was the exciting moment (eureka moment) during your research?

We could not get skeletal tissues at the post-natal stages since Osx-Cre mediated Stat3 knockout in osteoprogenitor cells causes lethality in neonates. Interestingly, when pregnant females and later pups were treated with BIO, a small molecule inhibitor of GSK3b, the skeletal phenotypes of loss of Stat3 were rescued and it was indeed a eureka moment for us. We could see that Stat3 knockout mouse pups were able to survive postnatally. This enabled us to study the post-natal skeletal defects upon Stat3 loss of function.

What do you hope to do next?

My current research aims to elucidate the roles of the key signaling pathways involved in the hypertrophic differentiation of chondrocytes. Most of the long bones in our body are formed by a process known as endochondral ossification, involving a transient cartilage template to make future long bones. This transient cartilage later undergoes hypertrophic differentiation and eventually gets replaced by the bone. The hypertrophic differentiation of the chondrocytes is a highly coordinated and molecularly regulated process. Any perturbation in this regulation may lead to various skeleton anomalies such as rickets and osteomalacia. Rickets primarily affects children and are characterized by developing poor, soft, and weak bones, leading to bone deformities. In adults, a similar condition is known as osteomalacia or soft bones. Therefore, detailed insight into the molecular regulation of hypertrophic differentiation of chondrocytes is required to understand the pathophysiology of skeletal-related disorders and I would like to pursue this in future.

Where do you seek scientific inspiration?

It’s nearly impossible to live a single day in our life that does not require scientific interventions. Thus, science is everywhere, and it is changing the world on a day-to-day basis, starting from the internet, mobile, Google, genomics, climate change, stem cells, energy, carbon dioxide, water, etc. The scientific discoveries inspire me the most, for example, vaccine development for Covid-19. The first case of Covid-19 was reported in Wuhan, China, in December 2019, and just within a year, hundreds of COVID-19 vaccine candidates were developed using various unrelated approaches and some of them reached the stage of human trials. All of this could happen because of the long-term investment into basic research and our belief in science and technology, and eventually we could vaccinate many individuals to help us combat this deadly pandemic. I think science is interesting because it provides opportunities to learn, make relevant observations and then use it in addressing the relevant questions.

How do you intend to help Indian science improve?

A developing country like India requires more scientific innovations to solve the problems and meet the demands. Therefore, early exposure to Science, Technology, Engineering, and Mathematics (STEM) is necessary to ignite young minds. This would encourage more people to come forward and believe in scientific innovation. I also believe that including more multidisciplinary approaches that involve inputs from all the possible branches of science could certainly improve scientific research in our country. This would be my mantra whenever I have the opportunity to improve teaching and research in my country.

Reference

P. S. Yadav et al., Stat3 loss in mesenchymal progenitors causes Job syndrome-like skeletal defects by reducing Wnt/beta-catenin signaling. Proc Natl Acad Sci U S A 118 (2021).

Edited by: Neha Varshney

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