The Skeleton: A Foundation for Wellbeing

Gaining a deeper understanding of the skeleton's connection with the body

Anyone who has fractured a bone understands the intensity of pain bone injuries induce and the extensive time required to heal. Although bones were once thought to simply provide a protective scaffold for the more fragile soft organs, bones actually contribute to many key biological processes including blood formation and metabolism. Bones are one of the most complex tissues in the body because of the multitude of structures, cell types, and matrix proteins. In addition, the functions of some of the cell types found in and around bone remain unknown, and even less is known about human bone formation because of the lack of suitable human models. We are thus currently limited in our ability to prevent or treat skeletal diseases.

Dr. Edward Hsiao, Assistant Professor of Medicine at the University of California, San Francisco, studies the skeleton to understand how different organs in the human body integrate together to control bone and tissue growth. By examining the pathways that allow the body to sense injuries and regulate the skeletal repair, Dr. Hsiao hopes to establish a foundation for preventing and treating diseases both in and out of the skeleton.

Human skeletal formation is genetically complex. Many skeletal traits and diseases (e.g., height and osteoporosis) are determined by multiple genes, thus making it difficult to understand how an individual gene may contribute to the final disease. Human diseases caused by mutations in a single gene provide an unparalleled opportunity to test how single genetic changes affect complex organs, such as bone, and provide a way to dissect the specific functions of key pathways. Dr. Hsiao and his team use samples from patients with genetic diseases as a way to identify the key genetic regulators that control human bone formation and function. As the team establishes new tools to  study human bone growth in  the laboratory, the methods, cells, and the growth factors developed through their work will also help identify the key cells and genes that could be targeted in a patient to activate endogenous tissue repair and regeneration. This would open up the possibility of repairing a skeleton or skeletal defect in a patient, with the long-term goal of repairing bone with the appropriate shape, in the correct location, and with the appropriate structural integrity. Ultimately, Dr. Hsiao’s discoveries will allow the team to better identify potential and novel therapeutic targets for both rare and common diseases.

Dr. Hsiao’s research currently focuses on several key questions:

  • How is bone part of the integrated system that controls normal homeostasis? Dr. Hsiao’s lab is interested in understanding how bone influences metabolism as an endocrine organ, and not merely as a scaffold for body structure. For example, G-protein coupled receptors are a major class of hormone molecules that regulate a wide variety of biological functions. Dr. Hsiao and his team are working to understand how abnormal activation or loss of function in G-protein coupled receptors cause human disease, including in bone formation, blood formation, and energy balance. Using a model system that resembles an "artificial hormone," the team can turn on and off the signaling with a synthetic drug. These studies are helping show how bone acts as an endocrine organ, how bone and blood development are intertwined, and how changes in bone hormone signaling lead to human diseases such as McCune-Albright syndrome (MAS) and osteoporosis. Through these findings, Dr. Hsiao and his team are now able to develop new tools and methods for studying tissue-specific stem cells, which will help elucidate how hormone signals made by bone affect other tissues such as fat, muscle, cartilage, and blood vessels.
  • Revealing how hormones control bone and tissue development: Hormone signaling is one critical way nature facilitates communication between cells; it plays an important role in maintaining normal homeostasis and in responses to environmental cues. Despite this central role for hormones, a detailed understanding of how hormone signals affect many tissues and cells remains lacking. Therefore, Dr. Hsiao is particularly interested in understanding how hormone regulatory signals control stem cell development in normal growth and disease, using the skeleton as a model system. Although the skeleton has traditionally been associated with mesenchymal stem cells, which can form bone, cartilage, and fat, there is growing recognition that other stem cells reside in the skeletal system. These stem cells are critical for the normal expansion of the skeleton as organisms grow, repairing the skeletal tissues after injury, and contributing to abnormal bone formation in some diseases. Using a combination of clinical insights, genetics, mouse models, and human embryonic stem (ES) and induced pluripotent stem (iPS) cells, Dr. Hsiao provides a patient-inspired, bedside-to-bench-back-to-bedside approach to understanding skeletal stem cell function.
  • Patient-inspired identification of new mutations that cause skeletal and hormonal diseases in humans: Traditionally, skeletal diseases have been difficult to study because of the complex genetic interactions that occur between many different genes. By directly examining patients with rare disorders using high-throughput sequencing methods, Dr. Hsiao and his lab hope to be able to identify the genes that cause these debilitating conditions as well as identify new targets for potential therapies to treat both rare diseases and common conditions.
  • Designing strategies to build artificial organs and bones: Dr. Hsiao’s other projects help identify the different cell types of hormonal signals that might control tissue development. Ultimately, one of his goals is to combine those together with newer tissue engineering technologies with the long-term goal of trying to make a complex organ in vitro such as the bone.

Bio

Dr. Edward Hsiao has always been interested in understanding how things work. This natural curiosity led him to pursue a career in science, where he could pursue three goals: 1) understanding how nature comes up with elegant ways to control normal development; 2) identifying how diseases develop when normal processes go awry; and 3) translating this knowledge into ways to help improve human health and quality of life.

Dr. Hsiao’s long-term goal is to be a leading physician-scientist with a robust, innovative, and clinically relevant research program. His research combines a patient-inspired approach with advanced genetic and cell biology methods to understand human skeletal development and disease pathogenesis. His goal is to gain new insights and apply them to develop better prevention and treatment strategies for a wide variety of medically-important diseases in and out of the skeleton.

Dr. Hsiao’s prior training established a solid foundation to achieve his career goals. He developed a strong clinical background in endocrinology; rigorous basic research using engineered G-protein coupled receptors (GPCRs); and translational applications using human induced pluripotent stem (iPS) cells to model diseases. He also helps direct the UCSF Metabolic Bone Clinic in the Division of Endocrinology and Metabolism. He also enjoys “thinking outside the box,” pursuing challenging questions, fostering productive collaborations, and leading a productive team. These wonderful experiences have helped him develop the confidence to take on challenges that require creative approaches.

Dr. Hsiao is excited by the recent advances in human genomics and human stem cells. Next-generation sequencing is discovering how nature elegantly regulates genomics. In addition, human iPS cells provide an unparalleled opportunity to develop human-specific disease models and the components to create multicellular tissues. Dr. Hsiao remarks, “These advances facilitate a robust cross-fertilization between clinical studies and bench research that I am striving to incorporate into my career as a physician scientist. This new knowledge will also help fulfill my dream of finding therapies for treating medically-important human conditions, and help position my research and clinical activities to be at the forefront of translational skeletal research.”

Aside from his research, Dr. Hsiao sincerely enjoys teaching and spending time outdoors hiking and mountain biking. He is also an avid photographer.

For more information, visit his website at endocrine.ucsf.edu/hsiaolab

Awards

J. Haddad Young Investigator Award, 2007

The American Society of Bone and Mineral Research

Young Investigator Award, 2007

American Society of Bone and Mineral Research, 29th Annual

Sandler Postdoctoral Research Fellowship Award, 2007–2008

University of California, San Francisco

Award of Excellence in Scientific Leadership, 2009

Gladstone Institute of Cardiovascular Disease, San Francisco, CA

March of Dimes Basil O’Connor Starter Award, 2012

Doris Duke Clinical Scientist Development Award, 2014

Patents

U.S. Patent No. 6,420,543 (Issued): "Growth differentiation factor-15 (GDF-15) polynucleotide sequence and amino acid sequence are provided herein."

Also described are diagnostic and therapeutic methods of using GDF-15 polypeptide and polynucleotide sequences.