The mission of our Musculoskeletal Research Laboratory is to use our deeply rooted culture of innovation, groundbreaking research, and advanced clinical care to advance our understanding of human musculoskeltal diseases, and find effective treatments for these conditions.

Musculoskeletal disorders are a growing health problem in both children and adults. Arthritis or chronic joint symptoms are reported by over 70 million Americans each year and lead to impaired quality of life. Osteoporosis affects over 10 million people in the United States and contributes to 9 million fractures worldwide each year. Bone fractures constitute over 3 million emergency department visits a year in the United States. Unfortunately, elucidating the mechanisms that regulate skeletal formation and repair remains challenging, but is crucial for understanding the pathologic changes in these diseases and for developing new treatments.

The long-term goal of our research is to define the genetic, hormonal, and environmental bases for human skeletal formation and identify new therapies for human skeletal diseases. Our research is inspired by patients with inherited skeletal diseases as a way to understand the critical mechanisms that regulate human skeletal formation. We are currently focusing on the hormone and regulatory signals that control the formation and function of mesenchymal tissues in normal skeletal growth and in disease, and how the immune system and microbiome affect mesenchymal tissue foramtion and repair. We use a combination of human, mouse, and cell culture models in our studies. Although our studies often start with very rare diseases, they provide crucial insight into normal development and disease pathogenesis, helping us understand more common but complex diseases such as osteoporosis, atherosclerosis, heterotopic ossification, and fracture repair.

Main Areas of Research

G-Protein coupled receptor (GPCR) signaling

G-protein-coupled receptors (GPCRs) are a major class of hormone signaling molecules. Our recent research has focused on how GPCR signals affect the normal and pathologic formation of bone, using a combination of mouse and embryonic stem cell models.

GPCRs signal through a select number of canonical pathways, including the G_s and G_i pathways, which increase and decrease intracellular cAMP levels by acting on adenylate cyclase. The timing and signaling of G-protein pathways can be experimentally manipulated by using designer receptors, such as receptors activated solely by synthetic ligands (RASSLs). We use these RASSLs as "artificial hormone systems" to dissect the roles of G-protein signaling in tissue development and function. This strategy allows us to analyze specific pathways that control cell and organ function in complex systems such as whole organs or in animal models such as mice.

We used this method to develop the ColI/Rs1 mouse model of fibrous dysplasia of the bone. The RASSL “Rs1” has constitutive G_s signaling activity, providing an ideal way to deliver prolonged and continuous activation of G_s signaling in tissues. In vivo, Rs1 expression in osteoblasts induces a dramatic increase in bone formation, but only if Rs1 is expressed before puberty. This age dependence was overcome by activating the Rs1 receptor with a synthetic ligand in adult mice. Stopping Rs1 activity reversed the bone phenotype. This model recapitulates many aspects of fibrous dysplasia of the bone. We continue to identify the molecular mechanisms regulating this phenotype, and if these pathways can be used to improve osteoblast function in fracture repair, hematopoiesis, and metabolism. We are also using advanced genetic methods like single cell sequencing and spatial transcriptomics to understand how GPCR signaling in different bone compartments ultimately drive bone formation. In addition, we recently identified several native GPCRs that have no known role in the skeleton but may be important regulators of bone formation. These are promising targets for treating pathological calcification or fibrous dysplasia.

Bone morphogenetic protein (BMP) pathways

The bone morphogenetic proteins (BMPs) are major regulators of cellular differentiation and function. We are studying how activating mutations in the ACVR1 gene result in the massive and progressive heterotopic ossification seen in patients with fibrodysplasia ossificans progressiva (FOP). Our team has identifed that ACVR1 activating mutations result in changes in cell fate stability. In addition, ACVR1 is critical for macrophage function, and activating mutations in ACVR1 lead to increased inflammatory responses in human macrophages. ACVR1 is also a major driver of abnormal sensory neuron function and may be a key contributor to different types of neuropathic pain. Our team has also been working to identify genetic modifiers in the ACVR1 signaling pathway that may be important modulators of bone disease, and identifying how environmental factors like the microbiome impact the ACVR1 pathway to lead to differences in disease penetrance.

Human induced pluripotent stem (iPS) cells

Our lab also takes a "bench-to-bedside" approach by studying clinical samples and patients with our ongoing bench research. For many human diseases, obtaining tissue samples can be difficult. Human induced pluripotent stem (iPS) cells are an attractive way to model congenital genetic diseases, as pluripotent stem cells can be derived from patients with genetic mutations. We are developing a collection of human iPS cells from different genetic diseases of abnormal bone formation, such as fibrodysplasia ossificans progresiva (FOP), a debilitating disease where heterotopic bone develops in soft tissues such as muscle as a result of a mutation in the BMP signaling pathway. Despite the dramatic clinical presentation, no robust human in vitro models or effective treatments are available.

We have created and refined a number of tools to help utilize these cells as the first human models for some of these skeletal diseases. Our studies are providing exciting insights into the key cellular and molecular causes of bone-related diseases including FOP, heterotopic ossification, vascular calcification/atherosclerosis, and inflammatory bone disease. Elucidating these interactions will help us understand what controls the formation and function of major mesenchymal tissues in the skeleton, including bone, cartilage, fat, muscle, macrophages, and blood vessels. Our long-term goal is to translate this information into new therapies for human diseases.

Clinical Research, Genomics, and Human Genetics

Dr. Hsiao's current clinical research is focused on metabolic bone disorders including fibrodysplasia ossificans progressiva (FOP) and fibrous dysplasia (FD) of the bone. We have several ongoing studies, including patient registries and biobanking to assist with basic translational projects to understand human disease pathogenesis. Our team is also involved in several interventional studies focused on treatments for rare bone diseases. Our team also seeks to understand and identify novel genetic factors that contribute to bone diseases. We are combining our human iPS cell expertise with a variety of state-of-the-art methods to identify and link genes to a disease phenotype. We recently identified a number of genes with no previously-known functions in bone, as well as genetic modifiers of known disease causing pathways. These candidates are being validated using a combination of human stem cell and mouse models.