Jh Duncan Bassett

Publications (2)6.04 Total impact

• Article: Genetic evidence that thyroid hormone is indispensable for prepubertal insulin-like growth factor-I expression and bone acquisition in mice.

  Weirong Xing, Kristen E Govoni, Leah Rae Donahue, Chandrasekhar Kesavan, Jon Wergedal, Carlin Long, J H Duncan Bassett, Apostolos Gogakos, Anna Wojcicka, Graham R Williams, Subburaman Mohan
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  ABSTRACT: Understanding how bone growth is regulated by hormonal and mechanical factors during early growth periods is important for optimizing the attainment of peak bone mass to prevent or postpone the occurrence of fragility fractures later in life. Using genetic mouse models that are deficient in thyroid hormone (TH) (Tshr(-/-) and Duox2(-/-)), growth hormone (GH) (Ghrhr(lit/lit)), or both (Tshr(-/-); Ghrhr(lit/lit)), we demonstrate that there is an important period prior to puberty when the effects of GH are surprisingly small and TH plays a critical role in the regulation of skeletal growth. Daily administration of T3/T4 during days 5 to 14, the time when serum levels of T3 increase rapidly in mice, rescued the skeletal deficit in TH-deficient mice but not in mice lacking both TH and GH. However, treatment of double-mutant mice with both GH and T3/T4 rescued the bone density deficit. Increased body fat in the TH-deficient as well as TH/GH double-mutant mice was rescued by T3/T4 treatment during days 5 to 14. In vitro studies in osteoblasts revealed that T3 in the presence of TH receptor (TR) α1 bound to a TH response element in intron 1 of the IGF-I gene to stimulate transcription. In vivo studies using TRα and TRβ knockout mice revealed evidence for differential regulation of insulin-like growth factor (IGF)-I expression by the two receptors. Furthermore, blockade of IGF-I action partially inhibited the biological effects of TH, thus suggesting that both IGF-I-dependent and IGF-I-independent mechanisms contribute to TH effects on prepubertal bone acquisition.
  Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 05/2012; 27(5):1067-79. · 6.04 Impact Factor
• Article: Bone signaling pathways and treatment of osteoporosis

  Apostolos I Gogakos, Moira S Cheung, JH Duncan Bassett, Graham R Williams
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  ABSTRACT: Osteoporotic fractures are a major healthcare burden costing over US$50 billion/per year. Bone turnover is a continuous process regulated by the coupled activities of osteocytes, osteoclasts and osteoblasts that maintain bone mass and strength. Osteoclastic bone resorption is regulated by the RANKL/osteoprotegerin/RANK pathway, while osteoblastic bone formation is controlled by canonical Wnt signaling. Antiresorptive bisphosphonates remain the mainstay of treatment but recombinant parathyroid hormone is increasingly being used as an anabolic agent. Nevertheless, these drugs are limited by patient compliance, efficacy and cost. Cathepsin K inhibitors and RANKL antibodies have been developed as new antiresorptive drugs, while short-acting calcilytics and antibodies to Dickkopf-1 and sclerostin are promising anabolics. The recent identification of adipocytes and duodenal enterochromaffin cells as novel regulators of bone mass represent exciting opportunities for future drug development.
  Expert Review of Endocrinology &amp Metabolism 10/2009; 4(6):639-650.