Translational Research Program in Pediatric Orthopaedics

Researchers in the Translational Research Program in Pediatric Orthopaedics at Children’s Hospital of Philadelphia are investigating the mechanisms that control skeletal development and growth, morphogenesis, and homeostasis in fetal and postnatal life. Their focus is on how skeletal elements and joints acquire their distinct organization and structure; how the skeletal tissues maintain their function and homeostasis over age; how bones and joints interact with muscles, tendons, and ligaments to sustain normal skeletal mobility; and how all these mechanisms and processes are regulated at the cellular, biochemical, and molecular levels.

Data and insights gained from those basic fundamental studies help us to envision what may be the pathogenic mechanisms of pediatric and adolescent musculoskeletal diseases, including growth deficiencies, synovial joint defects, metabolic bone diseases, Hajdu Cheney syndrome, Hereditary Multiple Exostoses, Lamb-Shaffer syndrome, and Fibrodysplasia Ossificans Progressiva. Researchers explore those predictions by working with animal models of disease.

Some additional research topics in the program are temporomandibular joint roles of SOX8 and SOX9 (SOXE proteins), chondrodysplasias, dwarfism, osteoarthritis, roles of SOX4 and SOX11 (SOXC proteins), skeletal dysplasias, cleft palate, congenital skeletal conditions, translational medicine therapies, and heterotopic ossification.

The ultimate goal is to create novel and effective biologic treatment strategies — that could be used solely or in combination with surgical interventions — to provide effective, safe, and long-lasting treatments and possibly a cure for those diseases.

Research Project Highlights:

• Synovial joint development. The synovial joints are essential for body motion, normal activities, and quality of life. Much is known about the structure, composition, and organization of their components, but far less is known about how the joints actually form during development. Pioneering work from our group has identified a specific subset of progenitor cells — collectively called the interzone — that emerge at each prospective joint formation site in the early fetus and then give rise to the joints.
• Heterotopic Ossification (HO) and Fibrodysplasia Ossificans Progressiva (FOP). These related musculoskeletal disorders involve the formation of excess skeletal tissue at abnormal anatomical locations. HO is caused by severe trauma, burns and/or immobilization, or follow invasive surgeries. FOP is a congenital and extremely aggressive pediatric form of HO. Dr. Pacifici and colleagues developed a potential FOP therapy involving a synthetic industry-made retinoid agonist now in a Phase III pharmaceutical clinical trial with colleagues at the University of Pennsylvania.
• Hereditary Multiple Exostoses (HME), or multiple osteochondromas, is a pediatric skeletal disease characterized by benign cartilaginous tumors that form next to growth areas of the skeleton in children and young adults and can cause health problems due to their location, size, and number. In some patients, the tumors transform into malignant chondrosarcomas and become life threatening. We have created genetic mouse models of the disease, investigated mechanisms of tumor formation, and are testing possible treatments.
• Temporomandibular joint (TMJ)-development and postnatal maintenance. Mandibular condylar cartilage is essential for functioning of the TMJ and its congenital or acquired aberrations can cause disease, including early onset osteoarthritis. We demonstrated that Hedgehog signaling is essential to condylar growth, both structural and functional.
• Skeletal stem cells and progenitors are the source for skeletal growth and remodeling.  Loss of stem/progenitor cells or their favorite microenvironment (niche) can severely impact the size and/or function of skeletal tissues. We have uncovered a pool of skeletal progenitors in the growing bones and also identified Hedgehog as an important niche signal.
• Congenital osteoporosis and osteosclerosis. Certain genetic conditions significantly weaken bones and cause fractures in children. For example, mutations in the gene Lrp5 cause the Osteoporosis-Pseudoglioma syndrome characterized by childhood osteoporosis; conversely, another set of mutations in the same gene leads to excessive bone. Our findings highlight the critical importance of Lrp5 and the related Wnt signaling pathway in bone, provide mechanistic insights into how Wnt signaling controls bone formation, and may lead to new directions for drug development.
• Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant skeletal disorder characterized prominent bone defects including general osteoporosis and acroosteolysis that manifest during childhood. Genetic studies have identified Notch2 as the disease gene, but current treatments are ineffective, partly because the cellular mechanisms for the defects are not fully understood. Our current studies are designed to fill the knowledge gap in the hope of discovering novel therapies.
• Diabetes and bone metabolism. Bone frailty has increasingly been recognized as a comorbidity of diabetes in both children and adults. Effective treatments of skeleton complications will ultimately depend on a clear understanding of the pathogenesis at the cellular level. We are currently investigating bone metabolism in diabetic animal models with the hope to develop safe bone therapeutics to fulfill the largely unmet need in children.
• Roles of SOX8 and SOX9 (SOXE proteins) in cell specification in growth plate and articular cartilage in normal processes and in skeletal malformation and degenerative joint diseases.
• Roles of SOX4 and SOX11 (SOXC proteins) in skeletal progenitor/stem cells in skeleton development and bone formation through adulthood, and in such diseases as skeletal dysplasias and osteoporosis.
• Developmental diseases due to SOX gene mutations. Study of underlying molecular mechanisms and search for therapeutic treatments for neurodevelopmental syndromes associated with mild dysmorphism and due to mutations in SOX5 (LAMSHF syndrome), SOX4 or SOX11.
• Structure/function analysis of SOX proteins with emphasis on discovering molecular partners and regulators of the proteins and how missense mutations cause skeletal, neurodevelopmental, and other diseases.v