Osteogenesis Imperfecta (OI) is the most common form of brittle bone disease and displays a spectrum of severity from mild phenotypes to severe early lethality. Key clinical features of OI are bone fragility and low bone mass. This fellowship focuses on a gene, SERPINF1 (serpin peptidase inhibitor, clade F, member 1), in which mutations cause a unique form of OI (type VI). OI type VI is characterized by un- mineralized osteoid and the fish-scale pattern of bone lamellation, which are pathologically distinct from other forms of OI. SERPINF1 encodes pigment epithelium-derived factor (PEDF) which is extensively studied as an anti-angiogenic, neurotrophic, and neuroprotective factor. Although PEDF is expressed in major cell types of skeletal tissue including osteoblasts, osteoclasts, and chondrocytes, its function in bone homeostasis is unknown. Therefore, the goal of this proposal is to elucidate the role of PEDF in bone homeostasis and determine the mechanism by which null mutations of this gene lead to OI type VI. I will also evaluate the therapeutic potential of exogenously delivered PEDF using mouse models. In the preliminary data, PEDF knockout mice show reduced bone volume and increased the expression level of MEPE, a negative regulator of bone mineralization. Based on preliminary data, I hypothesize that loss of PEDF alters intracellular signaling which regulates the function of osteoblasts and osteocytes, thus resulting in abnormal bone mineralization. I will test this hypothesis by investigating the PEDF loss- and gain-of-function mouse models and by evaluating cell signaling defects in the absence of PEDF. This research will not only elucidate a novel regulatory mechanism for bone mineralization, but also establish the pathogenic mechanism of OI type VI, thus providing potential therapeutic strategies for patients with OI type VI.
This project serves to elucidate the role of the gene, serpin peptidase inhibitor, clade F, member 1, (SERPINF1) which encodes the protein pigment epithelium-derived factor (PEDF). The loss of PEDF results in Osteogenesis Imperfecta type VI (OI type VI) which is a form of brittle bone disease. Through this research we hope to discover novel function of PEDF in bone homeostasis and pathogenic mechanism of OI type VI, potentially leading to new targets for therapeutics.
|Rajagopal, Abbhirami; Homan, Erica P; Joeng, Kyu Sang et al. (2016) Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice. Mol Genet Metab 117:378-82|
|Hudson, David M; Joeng, Kyu Sang; Werther, Rachel et al. (2015) Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human LEPREL1 mutations. J Biol Chem 290:8613-22|
|Joeng, Kyu Sang; Lee, Yi-Chien; Jiang, Ming-Ming et al. (2014) The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations. Hum Mol Genet 23:4035-42|
|Laine, Christine M; Joeng, Kyu Sang; Campeau, Philippe M et al. (2013) WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med 368:1809-16|