Led by Lilian Plotkin, PhD, the Plotkin Lab focuses on the role of connexins in the transduction of signals induced by hormonal, pharmacotherapeutic and mechanical stimuli in osteoblasts and osteocytes. For this, the laboratory utilizes in vitro techniques including tissue culture, analysis of protein expression by Western blotting and of gene expression by real time PCR. In addition, ex vivo cultures of bone cells isolated from mice treated with pharmacologic and hormonal agents, and from genetically modified mice are performed. Lastly, genetically modified mice have been generated and their bone phenotype is characterized using in vivo and ex vivo imaging, gene expression techniques and histomorphometric analysis.
As a result of this work, the laboratory has demonstrated that bisphosphonates, agents widely used to treat osteoporosis, prevent osteocyte and osteoblast apoptosis via a novel mechanism that involves opening of connexin43 hemichannel and activation of intracellular signaling molecules. The lab has unveiled a new role of connexin43 on the maintenance of osteocyte viability and in the composition of the bone matrix. Moreover, it has linked for the first time changes on the molecular composition of the cells in bone with cell death and deficient material properties. More recently, the laboratory has begun exploring the interaction between the brain and bone, by testing the consequences of neurological diseases, including epilepsy and fragile X syndrome, in the skeleton using mouse and rat models.
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Osteocyte apoptosis and regulation of bone resorption with aging
The objective of this application is to investigate the molecular mechanisms by which increased osteocyte apoptosis in Cx43-deficient and old mice results in targeted bone resorption. Plotkin Principal Investigator, R01- AR067210, NIH/NIAMS, 04/01/15-03/31/20
Bone defects in FMR1 deficient mice, a model of autism.
The purpose of this study is to characterize the basis for the reduced bone mass observed in mice lacking FRM1, the gene responsible for fragile X syndrome. Plotkin, Principal Investigator, IUPUI Office of the Vice Chancellor for Research – Research Support Funds Grant, 02/01/17-01/31/18
Research Funding
R01- AR067210, NIH/NIAMS, 04/01/15-03/31/20
Graduate Training Fellowship (T32-AR065971) to Alyson L. Essex (co-directed with Andrea Bonetto, PhD), 09/01/19-08/31/21\
Cagiantas Scholarship from the Indiana University School of Medicine to Hannah M. Davis, 09/01/18-08/31/19
Recent Publications
Plotkin LI, Davis HM, Essex AL. RAGE signaling in musculoskeletal biology. Skeletal Biology and Regulation Section in Current Osteoporosis Reports section, Current Osteoporosis Reports (M Forwood and A Robling, Section Editors, D Burr, Editor in Chief) doi: 10.1007/s11914-019-00499-w, in press, 2019.
Bullock WA, Plotkin LI, Robling AG, Pavalko FM. Mechanotransduction in bone formation/maintenance. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 9th Edition, (J. Bilezikian, editor), Wiley Blackwell, 75-83, 2019.
Bellido T, Plotkin LI, Bruzzaniti A. Bone Cells. In Basic and Applied Bone Biology (D.B. Burr and Allen MR, editors), Elsevier, in press, 2019.
Plotkin LI, Aguilar-Perez A, Bivi N. Local regulation of bone cell function. In Basic and Applied Bone Biology (D.B. Burr and Allen MR, editors), Elsevier, in press, 2019.
Plotkin LI, Davis, HM. Role of connexins and pannexins in bone and muscle mass and function. In Osteosarcopenia – Translational Research in Bone, Muscle and Fat Interactions (G. Luque, editor), Springer, in press, 2019.
Plotkin LI, Bruzzaniti A. Molecular signaling in bone cells: regulation cell differentiation and survival. In Advances in Protein Chemistry and Structural Biology – Intracellular signaling proteins (R. Donev, Editor). Elsevier, in press, 2019.
Davis HM, Aref MW, Aguilar-Perez A, Pacheco-Costa R, Allen K, Valdez S, Herrera C, Atkinson EG, Mohammad A, Lopez D, Harris MA, Harris SE, Allen MR, Bellido T, Plotkin LI. Cx43 overexpression in osteocytes prevents osteocyte apoptosis and preserves cortical bone quality in aging mice. Journal of Bone and Mineral Research Plus 2:206-216, 2018
Ansari SA, Jalali R, Plotkin LI, Bronckers A, DenBesten P, Zhang Y, Durlacher R, de Lange J, Rozema J. The importance of Connexin 43 in enamel development and mineralization. Frontiers in Physiology, Craniofacial Biology and Dental Research doi.org/10.3389/fphys.2018.00750, 2018
Pacheco-Costa R, Davis HM, Atkinson EG, Dilley JE, Byiringiro I, Aref MW, Allen MR, Bellido T, Plotkin LI. Reversal of loss of bone mass in old mice treated with mefloquine. Bone 114:22-31, 2018
Davis HM, Pacheco-Costa R, Plotkin LI. Response to R. L. Nevin “Considerations in the repurposing of mefloquine for prevention and treatment of osteoporosis”. Bone 146:306, 2018.
Plotkin LI, Davis, HM. MicroRNA regulation in osteocytes. MicroRNAs in Skeletal Development section, Current Molecular Biology Reports (A Delany, Editor, A van Wijnen, Editor in Chief) 4:191-197, 2018.
Davis HM, Pacheco-Costa R, Atkinson EG, Brun LR, Gortazar AR, Harris J, Hiasa M, Bolarinwa SA, Yoneda T, Ivan M, Bruzzaniti A, Bellido T, Plotkin LI. Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging. Aging Cell 16:551-563, 2017.
Pacheco-Costa R, Kadakia JR, Atkinson EG, Wallace JM, Plotkin LI, Reginato RD. Connexin37 deficiency alters organic bone matrix, cortical bone geometry, and increases Wnt/β-catenin signaling. Bone, 97:105–113, 2017.
Atkinson EG, Marcial A, Sanchez S, Porter C, Plotkin LI. MLO-Y4 osteocytic cell clones express distinct gene expression patterns characteristic of different stages of osteocyte differentiation. Actualizaciones en Osteología 13:207-213, 2017
Plotkin LI. Efectos divergentes del factor de crecimiento endotelial vascular, VEGF y el fragmento N-terminal de la proteína relacionada con la parathormona, PTHrP en células madre mesenquimales derivadas de tejido adiposo humano. Editorial for Revista de Osteoporosis y Metabolismo Mineral, 9:3-4, 2017.
Plotkin LI, Pacheco-Costa R, Davis HM. microRNAs and connexins in bone: interaction and mechanisms of delivery. Current Molecular Biology Reports 3:63-70, 2017.
Plotkin LI, Davis HM, Cisterna BA, Saez JC. Connexins and pannexins in bone and skeletal muscle. Current Osteoporosis Reports 15:326-334, 2017.
Hammond MA, Bernam AG, Pacheco-Costa R, Davis HM, Plotkin LI, Wallace JM. Removing or truncating connexin 43 in murine osteocytes alters cortical geometry, nanoscale morphology, and tissue mechanics in the tibia. Bone 88:85-91, 2016.
Pacheco-Costa R, Davis HM, Katchburian E, Atkinson EG, Plotkin LI, Reginato RD. Osteocytic connexin 43 is not required for the increase in bone mass induced by intermittent PTH administration in male mice. Journal of Musculoskeletal and Neuronal Interactions 16:47-57, 2016.
Plotkin LI, Gortazar AR, Bellido T. β-arrestin/connexin 43 complex anchors ERKs outside the nucleus: a pre-requisite for bisphosphonate anti-apoptotic effect mediated by Cx43/ERK in osteocytes. Actualizaciones en Osteología 12:11-20, 2016.
Plotkin LI, Laird DW, Amedee, J. Role of connexins and pannexins during ontogeny, regeneration, and pathologies of bone. BioMed Central – Cell Biology, 17:29-38, 2016.
Plotkin LI, Bellido T. Osteocytic signaling pathways as therapeutic targets for bone fragility. Nature Reviews Endocrinology, 12:593-605, 2016.
Plotkin LI, Gortazar AR, Davis HM, Condon KW, Gabilondo H, Maycas M, Allen MR, Bellido T. Inhibition of osteocyte apoptosis prevents the increase in osteocytic RANKL but it does not stop bone resorption or the loss of bone induced by unloading. Journal of Biological Chemistry. 290:18934-18942, 2015.
Pacheco-Costa R, Davis HM, Sorenson C, Hon MC, Hassan I, Reginato RD, Allen MR, Bellido T, Plotkin LI. Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain. Bone 81:632-643, 2015.
Pacheco-Costa R, Hassan I, Reginato RD, Davis HM, Bruzzaniti A, Allen MR, Plotkin LI. High Bone Mass in Mice Lacking Cx37 Due to Defective Osteoclast Differentiation. Journal of Biological Chemistry 289:8508-8520, 2014.
Bivi N, Pacheco-Costa R, Brun LR, Murphy TR, Farlow NR, Robling AG, Bellido T, Plotkin LI. Deletion of Cx43 selectively from osteocytes increases the osteogenic response to ulna loading in mice. Journal of Orthopaedic Research 31:1075-1081, 2013.
Bivi N, Nelson M, Faillace M, Li J, Miller LM, Plotkin LI. Deletion of Cx43 from osteocytes results in defective bone material properties and decreased strength in cortical bone. Calcified Tissue International 91:215-224, 2012.
Bivi N, Lezcano V, Romanello M, Bellido T, Plotkin LI. Connexin43 interacts with βarrestin: a pre-requisite for osteoblast survival induced by parathyroid hormone. Journal of Cellular Biochemistry 112:2920-2930, 2011. Featured as “Not to be missed” in IBMS BoneKEy 2011 Jul 1 doi:10.1138/20110518.
Bivi N, Condon K, Allen MR, Farlow N, Passeri G, Rhee Y, Bellido T, Plotkin LI. Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation. Journal of Bone and Mineral Research 27:374-389, 2012. Featured as “Not to be missed” in IBMS BoneKEy 2011 Nov 1 doi:10.1138/20110538.
