Laboratory of Jolene Windle, Ph.D.
A primary research focus in Dr. Windle’s laboratory is the use of genetically engineered mouse models to understand the pathogenesis of human disease.
A major area of interest involves analyzing the contribution of specific genetic alterations to various disease states in the bone involving abnormal osteoclast function, including Paget’s disease and myeloma bone disease. This group is investigating the role of the p62 (SQSTM1) gene in the increased formation and activity of osteoclasts seen in these bone disorders.
The p62 gene functions in multiple cytokine signaling pathways that lead to NF-ĸB activation in osteoclasts (including TNF-α, RANKL and IL-1), and mutations in the ubiquitin-associating (UBA) domain of p62 have been shown to contribute to the development of Paget’s disease. Dr. Windle’s group has developed both transgenic mice and, more recently, a p62P394L knock-in mouse, to accurately model this disease and investigate the mechanism by which p62 mutation contributes to its etiology.
These studies have demonstrated that mutations in the UBA domain function dominantly to stimulate NF-ĸB activation, and current studies are aimed at elucidating the mechanisms involved.
Additional studies are aimed at determining whether expression of mutant p62 in bone marrow stromal cells also contributes to the etiology of Paget’s disease. Studies are also ongoing to determine whether blocking p62 or other components of this signaling pathway can be used to impede the development of Paget’s disease or multiple myeloma bone disease.
As part of these studies, the team has developed mice that express luciferase specifically in osteoclasts and their precursors, and these are being interbred with various other lines to facilitate the analysis of osteoclast formation in vivo and in vitro.
In addition to these projects, Dr. Windle directs the VCU Transgenic/Knockout Mouse Core as well, which provides a wide range of services related to the production of genetically modified mice to VCU investigators. She is also involved in a number of collaborations with other members of the VIMM to develop transgenic and knockout mouse models for assessing the role of various genes in tumorigenesis (e.g., AEG-1), and to develop novel mouse models for enhanced optical imaging of tumor development and metastasis.
Transgenic Knockout Mouse Core Manager
Mark Subler, Ph.D.
Silbermann R, Bolzoni M, Storti P, Guasco D, Bonomini S, Zhou D, Wu J, Anderson JL, Windle JJ, Aversa F, Roodman GD, Giuiani N. Bone marrow monocyte-/macrophage-derived activin A mediates the osteoclastogenic effects of IL-3 in multiple myeloma. Leukemia, 2013, in press.
Teramachi J, Zhou H, Subler MA, Kitagawa Y, Galson DL, Dempster DW, Windle JJ, Kurihara N, Roodman GD. Increased IL-6 expression in osteoclasts is necessary but not sufficient for the development of Paget’s disease of bone. J Bone Miner Res, 2013, in press.
Sun Q, Sammut B, Wang F-M, Kurihara N, Windle JJ, Roodman GD, Galson DL. TBK1 mediates critical effects of measles virus nucleocapsid protein (MVNP) on pagetic osteoclast formation. J Bone Miner Res, 2013, 29:90-102.
Miller AV, Hicks MA, Nakajima W, Richardson AC, Windle JJ, Harada H. Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumors. PLoS One, 2013, 8(4):e60685.
Teramachi J, Hiruma Y, Ishizuka S, Ishizuka H, Brown JP, Michou L, Cao H, Galson DL, Subler MA, Zhou H, Dempster DW, Windle JJ, Roodman GD, Kurihara N. Role of ATF7-TAF12 interactions in the VDR hyper-sensitivity of osteoclast precursors in Paget’s disease. J Bone Miner Res, 2013, 28:1489-1500.
Wang F-M, Sarmasik A, Hiruma Y, Sun Q, Sammut B, Windle JJ, Roodman GD, Galson DL. Measles virus nucleocapsid protein, a key contributor to Paget’s disease, increases IL-6 expression via down-regulation of FoxO3/Sirt1 signaling. Bone, 2013, 53:269-276.
Srivastava J, Siddiq A, Emdad L, Santhekadur PK, Chen D, Gredler R, Shen XN, Dumur CL, Hylemon PB, Mukhopadhyay ND, Bhere D, Shah K, Ahmad R, Giashuddin S, Stafflinger J, Subler MA, Windle JJ, Fisher PB, Sarkar D. Astrocyte elevated gene-1 (AEG-1) promotes hepatocarcinogenesis: novel insights from a mouse model. Hepatology, 2012, 56:1782-1791.
Kovacs JR, Li C, Yang Q, Li G, Garcia IG, Ju S, Roodman DG, Windle JJ, Zhang X, Lu B. Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery. Cell Death Differ, 2012, 19:144-152.
Kurihara N, Hiruma Y, Yamana K, Michou L, Rousseau C, Morissette J, Galson DL, Teramachi J, Zhou H, Dempster DW, Windle JJ, Brown JP, Roodman GD. Contributions of the measles virus nucleocapsid gene and the SQSTM1/p62(P392L) mutation to Paget’s disease. Cell Metab, 2011, 13:23-34.
Ishizuka H, Garcia-Palacios V, Lu G, Subler MA, Zhang H, Boykin CS, Choi SJ, Zhao L, Patrene K, Galson DL, Blair HC, Hadi TM, Windle JJ, Kurihara N, Roodman GD. ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo. J Bone Min Res, 2011, 26:169-181.
Dossa T, Arabian A, Windle JJ, Dedhar S, Teitelbaum S, Ross F, Roodman GD, St-Arnaud R. Osteoclast-specific inactivation of the Integrin-Linked Kinase (ILK) inhibits bone resorption. J Cell Biochem, 2010, 110:960-967.
Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, Blair HC, Roodman GD. Osteoclasts are important for bone angiogenesis. Blood, 2010, 115:140-149.
Hiruma Y, Honjo T, Jelinek DF, Windle JJ, Shin J, Roodman GD, Kurihara N. Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation. Blood, 2009, 113:4894-4902.
Hiruma Y, Kurihara N, Subler MA, Zhou H, Boykin CS, Zhang H, Ishizuka S, Dempster DW, Roodman GD, Windle JJ. A SQSTM1/p62 mutation linked to Paget’s disease increases the osteoclastogenic potential of the bone microenvironment. Hum Mol Genet, 2008, 17:3708-3719.