The primary research of Dr. Tetradis focuses on gene expression and osteoporosis.
Osteoporosis inflicts significant morbidity and mortality, especially among postmenopausal women. The only anabolic treatment for osteoporosis is daily injections of parathyroid hormone (PTH), an endogenous peptide whose mechanism of action is unknown. This is not trivial because while PTH is anabolic when given intermittently, it is equally catabolic when given continuously and intermittent PTH greatly increases the relative risk for osteosarcomas in rats.
Dr. Sotirios Tetradis' working hypothesis is that PTH-activated osteoblasts undergo a cascade of gene expression beginning with primary genes followed by late genes that affect osteoblast differentiation and function. Tetradis and his colleagues have identified several PTH-induced primary genes and are studying a subset of those that are transcription factors because of their potential to mediate late gene expression.
E4BP4/NF-IL3, a basic leucine zipper transcriptional repressor, is involved in apoptosis, the anti-inflammatory response, and circadian rhythm regulation. The researchers found that PTH-induced E4BP4 protein binds to and inhibits E4BP4 response element (EBPRE)-containing promoters in osteoblasts. Interestingly, E4BP4 is induced by glucocorticoids and thyroid hormone, which are potent osteotropic hormones that regulate transcription through their respective nuclear receptors. Thus, interest in E4BP4 extends into the realm of nuclear receptor-activated osteoblast function.
Nuclear receptors also are of special interest to Tetradis' lab because he and his colleagues found that PTH induces NGFI-B nuclear orphan receptors in vitro and in vivo. Nurr1, Nur77 and NOR-1 are important for cellular differentiation and they target NGFI-B response element (NBRE)-containing promoters. Nurr1 transactivates the promoter of the osteoblast specific gene osteocalcin (OCN), while Nurr1-expressing adenovirus induces OCN mRNA in osteoblasts. The researchers are currently searching for co-activators that interact with NGFI-B proteins in the transactivation of target genes.
Tetradis' research has implications for the clinical problem of osteoporosis and the basic scientific problem of transcriptional regulation. He and his colleagues have established valuable collaborations throughout UCLA that will help their studies of the molecular cascades during osteoblast differentiation and function.
Selected Cancer-Related Publications:
Aghaloo TL, Amantea CM, Cowan CM, Richardson JA, Wu BM, Parhami F, Tetradis S. Oxysterols enhance osteoblast differentiation in vitro and bone healing in vivo. J Orthop Res. 2007.
Huang MS, Morony S, Lu J, Zhang Z, Bezouglaia O, Tseng W, Tetradis S, Demer LL, Tintut Y. Atherogenic phospholipids attenuate osteogenic signaling by BMP-2 and PTH in osteoblasts. J Biol Chem. 2007.
Richardson JA, Amantea CM, Kianmahd B, Tetradis S, Lieberman JR, Hahn TJ, Parhami F. Oxysterol-induced osteoblastic differentiation of pluripotent mesenchymal cells is mediated through a PKC- and PKA-dependent pathway. J Cell Biochem. 2007; 100(5): 1131-45.
Nervina JM, Magyar CE, Pirih FQ, Tetradis S. PGC-1alpha is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts. Bone. 2006.
Nervina JM, Camargo PM, Bezouglaia O, Tetradis S. Prostanoid- and interleukin-1-induced primary genes in cementoblastic cells. J Periodontol. 2006; 77(8): 1362-70.