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.