Bone defects in Shwachman-diamond Syndrome: cellular oe systemic impairment?

BONE DEFECTS IN SHWACHMAN-DIAMOND SYNDROME: CELLULAR OR SYSTEMIC IMPAIRMENT? Frattini A1, 2*, Villa I3, Valli R1, Montalbano G1, De Paoli E1, Bergami E4, Zecca M4, Pasquali F1, Maserati E1 1Human and Medical Genetics, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy; 2 Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy; 3Bone Metabolism Unit, San Raffaele Scientific Institute, Milan, Italy, 4Oncoematologia Pediatrica, IRCCS Policlinico San Matteo, Pavia, Italy Bone defects in Shwachman-Diamond syndrome (SDS) are characterized by abnormal development of growth plate and delay of secondary center of ossification that lead to a number of variable skeletal signs and early-onset low turnover osteoporosis. The few amount of published data has not yet clarified if the SDS bone defect is systemic or cell-autonomous. The goal of our project is to investigate the physiopathology of SDS bone defects, by clarifying if they are due to a systemic imbalance of hormones and cytokines that regulate cartilage and bone formation or to an imbalance of adipogenesis versus osteoblastogenesis, as reported in the conditional sbds mouse model. We obtained serum samples from blood of four Italian SDS patients, 3 male and 1 female (age 4-43 years) with a wide range of different skeletal manifestations. The importance of the GH/IGF1/PTH axis in skeletal growth is well known, whereas vitamin D plays an essential role in development and maintenance of a healthy mineralized skeleton. To define the possible role of a systemic defect we evaluated seric levels of Growth Hormone (GH), Insulin-Growth Factor 1 (IGF-1), Parathyroid Hormone (PTH), alkaline phosphatase (ALP), and Vitamin D. Our preliminary results showed quite normal levels in all our patients; one patient had low level of vitamin D. The limited number of patients analyzed does not allow to draw definite conclusions, but we may speculate that either the SDS bone defect is not systemic or that the systemic impairment may be limited during the infancy affecting the development of cartilage but is not significant in the adult. On the other hand, the bone defect may be due to an imbalance in differentiation of adipocytes vs osteoblasts (cell-autonomous defect): this study is in progress by the differentiation of mesenchymal stem cells obtained from bone marrow of SDS patients.