Osteogenesis Imperfecta (OI) is the most commonly inherited 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, whereas patients may also display blue sclera, dentinogenesis imperfecta, joint and skin laxity, hearing impairment and/or wormian bones on the skull [1]. Specifically, this fellowship focuses on a gene in which mutations result in recessive OI as well as Bruck Syndrome termed FK506 Binding Protein 10 (FKBP10) that encodes the FKBP65 protein [2, 3]. The FKBP65 protein complexes with Heat Shock Protein 47 (HSP47) and together they are thought to be involved in chaperoning of collagen in the endoplasmic reticulum [4, 5]. Currently, we do not understand the consequences of FKBP10 loss and its role in collagen and ECM formation. Therefore our goal is to elucidate the role of FKBP10 in the skeleton and how null mutations lead to progressively deforming OI. In other types of recessive OI, the biochemical modifications of collagen are altered, in particular by the complex of proteins consisting of Prolyl-3-Hydroxylase-1 (P3H1), Cartilage Associated Protein (CRTAP) and prolyl cis-trans isomerase cyclophilin-B (PPIB) [6]. Preliminary data concerning the Crtap knockout mice also suggests that there may be cell signaling defects in these mice. In addition, in vitro studies of human cells with FKPB10 loss show ER stress, fragmented Golgi, procollagen aggregates, and increased numbers of autophagosomes. This suggests that there may be strong cellular phenotypes and the unfolded protein response pathway may be affected. We hypothesize that due to changes in intracellular conditions owing to Fkbp10 loss, disruptions in cellular and possibly biochemical phenotypes lead to common mechanisms that may exist between different causes of OI due to the similarity in phenotypes.
We aim to test this hypothesis by determining the in vivo phenotypes of FKBP10 loss on skeletal and connective tissues, assessing the biochemical and cellular phenotypes of Fkbp10 null cells, and evaluating cell signaling defects in the absence of Fkbp10. This research is important for establishing common mechanisms of disease which may provide potential therapeutic targets for patients with OI and Bruck syndrome, especially through addressing altered cell signaling and altered collagen biochemistry which may affect it. The National Institute of Dental and Craniofacial Research is the recipient organization of this fellowship because OI and Bruck syndrome are characterized by craniofacial phenotypes.

Public Health Relevance

This project serves to elucidate the role of the loss of the gene FK506 Binding Protein 10 (FKBP10) which encodes the protein FKBP65 and complexes with Heat Shock Protein 47 (HSP47) in order to chaperone collagen in the extracellular matrix. This loss results in Bruck syndrome and progressively deforming recessive Osteogenesis Imperfecta (OI), a form of brittle bone disease. Through this research we hope to discover novel mechanisms of OI and commonalities that exist between various causes of OI, potentially leading to new targets for therapeutics.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Predoctoral Individual National Research Service Award (F31)
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NIDCR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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Baylor College of Medicine
Schools of Medicine
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Duran, Ivan; Martin, Jorge H; Weis, Mary Ann et al. (2017) A Chaperone Complex Formed by HSP47, FKBP65, and BiP Modulates Telopeptide Lysyl Hydroxylation of Type I Procollagen. J Bone Miner Res 32:1309-1319
Lietman, Caressa D; Lim, Joohyun; Grafe, Ingo et al. (2017) Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone. J Bone Miner Res 32:1354-1367
Grafe, Ingo; Alexander, Stefanie; Yang, Tao et al. (2016) Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta. J Bone Miner Res 31:1030-40
Lietman, Caressa D; Marom, Ronit; Munivez, Elda et al. (2015) A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. J Bone Miner Res 30:489-98
Duran, Ivan; Nevarez, Lisette; Sarukhanov, Anna et al. (2015) HSP47 and FKBP65 cooperate in the synthesis of type I procollagen. Hum Mol Genet 24:1918-28
Lietman, Caressa D; Rajagopal, Abbhirami; Homan, Erica P et al. (2014) Connective tissue alterations in Fkbp10-/- mice. Hum Mol Genet 23:4822-31
Grafe, Ingo; Yang, Tao; Alexander, Stefanie et al. (2014) Excessive transforming growth factor-? signaling is a common mechanism in osteogenesis imperfecta. Nat Med 20:670-5
Grover, Monica; Campeau, Philippe M; Lietman, Caressa Dee et al. (2013) Osteogenesis imperfecta without features of type V caused by a mutation in the IFITM5 gene. J Bone Miner Res 28:2333-7