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Dr. Pacifici’s biomedical research spans three decades and has explored mechanisms of skeletal development and growth in fetal and postnatal life. Specifically we focus on the identification of cellular and molecular mechanisms that regulate the differentiation of progenitor cells into distinct skeletal tissues -including articular cartilage- and permit the assembly of distinct skeletal structures including long bones, joints and vertebrae. The resulting information, insights and concepts are used to uncover and understand the pathogenesis of congenital and acquired skeletal disorders -including skeletal dysplasia- and to test possible therapeutic strategies in cell and animal models of human disease. Promising strategies ultimately provide the basis for clinical trials. The following examples represent ongoing projects and indicate how far they have progressed toward reaching their ultimate translational medicine and clinical goals.

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Synovial joint development and congenital defects

The synovial joints -including the elbow, hip, knee, and intervertebral joints- are obviously essential for body motion, normal activities and quality of life. Much is known about the structure, macromolecular composition and organization of their components, including articular cartilage, ligaments and synovial lining. However, much less is known about how the joints actually form in the developing fetus, are able to produce their distinct tissues, and acquire their diverse shapes and architectures each uniquely adept and adapted to specific body locations and motion requirement. 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 and their tissues (Figure 1). Ongoing work aims to uncover, define and characterize the cellular and molecular mechanisms that enable these progenitor cells to perform their remarkable developmental tasks and to give rise to diverse joints and specific tissues. It aims also to test whether those mechanisms could be exploited therapeutically to enhance joint tissue repair and regeneration and whether changes in those mechanisms subtend congenital pediatric joint disorders, including developmental dysplasia of the hip. These research lines have been, and continue to be, funded by the National Institutes of Health.

Heterotopic Ossification and Fibrodysplasia Ossificans Progressiva

These two related musculoskeletal disorders involve the formation of excess skeletal tissue at abnormal anatomical locations and often at the expense of other tissues such as muscles. HO is caused by severe trauma, burns and/or immobilization and as such, is prevalent in severely wounded soldiers in war zones. It can also follow invasive surgeries. FOP is a congenital and extremely aggressive pediatric form of HO and is caused by an activating mutation in bone morphogenetic protein receptor ALK2. The excess skeletal tissue forming in both FOP patients and many HO cases occurs via endochondral ossification and thus, involves progenitor cell differentiation into chondrocytes, formation of cartilage tissue, and replacement of cartilage by endochondral bone. Original studies carried out by Dr. Pacifici and colleagues several years back showed that natural retinoid agonists -such as all-trans-retinoic acid- can block chondrogenic cell differentiation which is the first step in excess skeletal tissue formation. Using such key insights and funding from the Department of Defense, Dr. Pacifici working closely with his Division colleague Dr. M. Iwamoto developed a potential therapy for FOP that involves synthetic industry-made retinoid agonists selective for the nuclear retinoic acid receptor alpha (RARa) or RARg. Agonists for RARg turned out to be far more potent and effective, and one of them –Palovarotene- is now fast moving toward a Phase II clinical trial for FOP patients organized with our colleagues at the University of Pennsylvania and the pharmaceutical company Clementia. Ongoing preclinical studies are testing the validity of the RARg agonist therapy in models of injury- and surgery-induced HO.

Hereditary Multiple Exostoses

Hereditary Multiple Exostoses (HME) is a pediatric skeletal disease characterized by benign cartilaginous tumors -called exostoses- that form next to the growth areas of the skeleton in children and young adults (Fig. 2). Because of their location, size and number, the exostoses can cause a number of health problems that include growth retardation, skeletal deformities, chronic pain, blood vessel and tendon compression, and early onset osteoarthritis. In some HME patients, the exostoses can transform into malignant osteosarcomas and thus become life threatening. Most cases of HME are caused by dominant loss-of-function mutations in EXT1 or EXT2 that are Golgi-associated glycosyl-synthases responsible for heparan sulfate (HS) synthesis, leading to systemic HS deficiency. Funding from the NIH has allowed us to create genetic mouse models of the disease, investigate possible mechanisms by which the exostoses form, and monitor exostosis long-term fate, behavior and consequences on the skeleton. These models are also allowing us to test possible therapeutic approaches by which exostosis formation could be prevented or halted. In collaboration with researchers in the Center for Advanced Genomics here at CHOP and researchers at other Institutions, we are also searching for additional culprits of the disease, including genetic modifiers that could contribute to disease progression and severity.

Terminal degrees: PhD

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