Rothmund-Thomson syndrome (RTS) is a mutisystem genetic disorder caused by mutations in the RECQL4 gene. Our previous studies characterizing this syndrome have led to several observations regarding bone defects in these patients. RTS patients have severe skeletal abnormalities, including osteopenia, hypoplastic or fused bones, and trabecular defects. They also have a significantly increased risk for developing osteosarcoma (OS), a primary malignant bone tumor for which new therapies are greatly needed. These bone conditions are increased when RECQL4 is mutated, suggesting that RECQL4 plays an important function in normal bone development and in suppression of OS. However, the exact function the RECQL4 DNA helicase and how it exerts its effects in normal bone cells and in bone tumors are not known. We have shown through yeast two-hybrid assay that RECQL4 interacts with PRICKLE1 protein, a member of the Wnt signaling pathway known to be important in both bone development and cancer. The objective of this proposal is to examine the skeletal consequences of loss of RECQL4 function both clinically and at the molecular and cellular level in order to define the mechanism of RECQL4 action in bone. To test our hypothesis that RECQL4 is a bone homeostasis protein that exerts its developmental and tumorigenic effects through the Wnt signaling pathway, we propose the following aims.
In Aim 1, we will characterize the human skeletal phenotype that results from loss of RECQL4 function in RTS patients through detailed clinical evaluation, including DXA scanning, biochemical bone turnover markers, and IV calcium labeling studies to assess bone formation and resorption.
In Aim 2, we will generate an osteoblast-specific Recql4 conditional knockout (CKO) mouse model to characterize the skeletal defects and cancer phenotypes in Recql4 deficient mice through detailed phenotypic and bone histomorphometric analyses.
In Aim 3, we will explore the effects of loss of RECQL4 function on Wnt signaling using in vitro assays of b-catenin activity and gene and protein expression analyses of the Wnt and related signaling pathways. Understanding the skeletal defects in RTS patients and the cellular events in terms of bone formation and resorption will allow us to define the molecular pathways in which RECQL4 participates and how it relates to bone development and tumorigenesis. Results of these studies will guide us in the treatment of RTS patients, provide insight into the mechanisms of bone disease, and may eventually provide opportunities for more targeted therapies for the treatment of OS and osteoporosis in the general population.

Public Health Relevance

The goal of our project is to study the role of the RECQL4 gene pathway in the development of osteosarcoma and other bone diseases such as osteoporosis. We will study patients with a human genetic disorder (Rothmund-Thomson syndrome) along with mouse models of RECQL4 deficiency to understand the cellular and molecular basis of skeletal dysplasia. This will allow us to discover novel ways to improve the treatment of osteosarcoma and osteoporosis in the general population.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Sharrock, William J
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Baylor College of Medicine
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United States
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Lin, Yu-Hsuan; Jewell, Brittany E; Gingold, Julian et al. (2017) Osteosarcoma: Molecular Pathogenesis and iPSC Modeling. Trends Mol Med 23:737-755
Cao, Felicia; Lu, Linchao; Abrams, Steven A et al. (2017) Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome. Hum Mol Genet 26:3046-3055
Lu, Linchao; Harutyunyan, Karine; Jin, Weidong et al. (2015) RECQL4 Regulates p53 Function In Vivo During Skeletogenesis. J Bone Miner Res 30:1077-89