Motyl Lab Members
Research Associate II
It is well-known that elevated sympathetic nervous system (SNS) activity (also known as the “fight-or-flight” response) reduces bone formation and increases resorption, resulting in bone loss. Therefore, elevated SNS activity via the action of β-adrenergic receptor (βAR) signaling has been implicated in pathologies such as osteoporosis. βAR antagonists (β-blockers) provide a potential target for preventing and/or treating osteoporosis. My work focuses on characterizing the direct effects of βAR activity in bone-resorbing osteoclasts to determine potential mechanisms by which βAR stimulation affects intracellular signaling and osteoclast differentiation, activity, and function.
Confocal image of an osteoclast expressing β-adrenergic receptor. Cells were isolated from the bone marrow of 6-week old mice and cultured for five days in osteoclast-differentiation media. Images were acquired at 63x magnification and staining was performed for the following: DAPI (nucleus; blue), Phalloidin (F-actin; green), and β-adrenergic receptor (anti-β-adrenergic receptor antibody; red). Pictured are three individual fluorescence channels and a composite overlay of all channels (bottom right corner). Osteoclasts form when precursor cells fuse together, resulting in large multinucleated cells that form a “sealing zone” and release several factors that break down the bone matrix.
Research Assistant II
Risperidone is an atypical antipsychotic (AA) drug that is used to treat schizophrenia and bipolar disorder as well as complications of dementia in older adults. Previous research has shown an association between AA treatment and fractures and falls in clinical studies, and mouse studies have shown that risperidone treatment induces bone loss. Interestingly, co-therapy with the beta-blocker propranolol significantly curtailed bone loss, suggesting bone loss is due to metabolic consequences of sympathetic nervous system activation. My research goal is to develop a mechanistic understanding of this process by collecting and analyzing multi-omics data including mRNA, proteomic, and lipidomic data to investigate the mechanism through which sympathetic activation leads to bone loss in risperidone-treated mice. Furthermore, I will develop a robust pipeline and new methods for integration of multi-omic data sources that may be applied to other datasets.
Motyl KJ, Beauchemin M, Barlow D, Le PT, Nagano K, Treyball A, Contractor A, Baron R, Rosen CJ, Houseknecht KL. A novel role for dopamine signaling in the pathogenesis of bone loss from the atypical antipsychotic drug risperidone in female mice. Bone. 2017; 103:168-176. PMID: 28689816
Carvalho AL, DeMambro VE, Guntur AR, Le P, Nagano K, Baron R, de Paula FJA, Motyl KJ. High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice. Journal of Cellular Physiology. 2017; PMID: 28631813
Irwin R, Lin HV, Motyl KJ, McCabe LR. Normal bone density obtained in the absence of insulin receptor expression in bone. Endocrinology. 147(12):5760-5767, 2006. Highlighted in Endocrine News
Motyl KJ and LR McCabe. Leptin treatment prevents type I diabetic marrow adiposity but not bone loss in mice. J Cell Physiol. 218(2): 376-384, 2009. Highlighted in Science Now http://news.sciencemag.org/sciencenow/2010/03/appetite-suppressor-could-be-an-.html
Motyl KJ*, S Botolin*, R Irwin*, T Kadakia, A Amalfitano, RC Schwartz, and LR McCabe. Bone inflammation and altered gene expression with type I diabetes early onset. J Cell Physiol. 218(3):575-583. *authors contributed equally
Motyl KJ, and LR McCabe. Streptozotocin, type I diabetes severity and bone. Biological Procedures Online. Published online: 06 March 2009.
Motyl KJ, Raetz M, Tekalur SA, Schwartz RC, McCabe LR. CCAAT/enhancer binding protein beta-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption. Am J Physiol Regul Integr Comp Physiol. 2011;300(5):R1250-60.
Motyl KJ, McCauley LK, McCabe LR. Amelioration of Type I Diabetes-induced Osteoporosis by Parathyroid Hormone is Associated with Improved Osteoblast Survival. J Cell Physiol. 2012 Apr;227(4):1326-34.
Motyl KJ*, Dick-de-Paula I*, Maloney AE, Lotinun S, Bornstein S, de Paula FJ, Baron R, Houseknecht KL, Rosen CJ. Trabecular bone loss after administration of the second-generation antipsychotic risperidone is independent of weight gain. Bone. 2012;Feb;50(2):490-8. *authors contributed equally
Motyl KJ, Bishop KA, Demambro VE, Bornstein SA, Le P, Kawai M, Lotinun S, Horowitz MC, Baron R, Bouxsein ML, Rosen CJ. Altered thermogenesis and impaired bone remodeling in Misty mice. J Bone Miner Res. 2013. 28(9):1885-97. PMCID: PMC3743939.
Devlin MJ, Van Vliet M, Motyl K, Karim L, Brooks DJ, Louis L, Conlon C, Rosen CJ, Bouxsein ML. Early-onset type 2 diabetes impairs skeletal acquisition in the male TALLYHO/JngJ mouse. Endocrinology. 2014. Oct;155(10):3806-16. PMCID: PMC4164927.
Motyl KJ, DeMambro VE, Barlow D, Olshan D, Nagano K, Baron R, Rosen CJ, Houseknecht, CJ. Propranolol attenuates trabecular bone loss in female mice from the atypical antipsychotic, risperidone. Endocrinology. 2015; 156(7):2374-83. PMID: 25853667. **highlighted in Endocrine News.
Zhang J, Motyl KJ, Irwin R, MacDougald OA, Britton RA and McCabe LR. Loss of bone and Wnt10b expression with type 1 diabetes is blocked by the probiotic L. reuteri. Endocrinology. 2015; 156(9):3169-82.
Rosen CJ, Motyl KJ. No bones about it: insulin modulates skeletal remodeling. Cell. 2010;142(2):198-200.
Motyl KJ, McCabe LR, Schwartz AV. Bone and glucose metabolism: A two-way street. Arch Biochem Biophys. 2010 Nov 1;503(1):2-10.
Motyl KJ, Rosen CJ. Temperatures rising: Brown fat and bone. Discov Med. 2011 Mar;11(58):179-85.
Motyl KJ, Rosen CJ. Understanding leptin-dependent regulation of skeletal homeostasis. Biochimie. 2012 Oct;94(10):2089-96.
Motyl KJ, Rosen CJ. The skeleton and the sympathetic nervous system: it’s about time! J Clin Endocrinol Metab. 2012 Nov;97(11):3908-11.
Calarge CA, Ivins SD, Motyl KJ, Shibli-Rahhal AA, Bliziotes MM, and Schlechte JA. Possible mechanisms for the skeletal effects of antipsychotics in children and adolescents. Therapeutic Advances in Psychopharmacology. 3(5): 278-93. 2013. PMCID: PMC3805387.