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Clemens Lab

3d rendering of normal bone structureNormal bone 3d rendering of osteoporotic bone structureOsteoporotic bone

The Clemens Lab, led by Thomas Clemens, Ph.D., conducts research focused on identification of the cellular and molecular mechanisms that mediate bone formation and repair. Currently, we are studying the role of sensory nerves in bone and the coupling of bone cell metabolic activity to the sensory nerves’ development and function.

The skeleton is one of the most important structures in our bodies. Bones allow us to stand, walk and move from one place to another, and they serve as protectors of our vital organs. With aging, the skeleton loses its bone mineral and develops cracks and discontinuity in the bone structure (the plates and rods comprising the bone). This degradation of the bone structure — osteoporosis — is a global health problem that we aim to better understand, treat and prevent with the help of research.

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Lab Projects

Roll of Sensory Nerves in Bone

illustration of mouse embryoSensory nerves in the developing mouse embryo.

Anyone who has broken a bone is aware of the existence and function of sensory nerves in bone. However, little is known about how nerves innervate the skeleton and what purpose beyond pain these nerves perform.

In this project, we will use several novel approaches to characterize the timing of innervation and the consequence of blocking nerve action on bone development and repair. These studies represent the first comprehensive approach to investigating the function of sensory nerves in bone. Our results are expected to yield new insights into their role.

Publications

  1. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral boneCell Reports, 2016; 16:2723-35. PMID: 27568565

  2. Tomlinson RE, Li Z, Li Z, Minichiello L, Riddle RC, Venkatesan A, Clemens TL. NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in miceProc Natl Acad Sci U S A, 2017 May 2; 114(18):E3632-E3641

Bone and Energy Metabolism

illustration of endocrine loop for an osteoblast and beta cellProposed bone pancreas endocrine loop.

Our recent studies suggest the existence of a novel endocrine regulatory loop through which insulin signaling in the osteoblast participates in the regulation of global energy metabolism. This project examines fuel consumption by osteoblasts and osteocytes under normal conditions and in response to well-defined stimuli, which increase bone cell energy demands. Such information will help clarify how and why bone communicates with other energy consuming tissues and may explain the close association between the existence of bone disease and diabetes in humans, which should have an immediate impact on the management, treatment and prevention of these related metabolic disturbances.

Publications

  1. Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere M-C, Hussain MA, Brüning, Thomas L Clemens, TL. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body compositionCell, 2010; 142:309-19
  2. Riddle RC, Frey JL, Tomlinson RE, Ferron M, Li Y, DiGirolamo DJ, Faugere MC, Hussain MA, Karsenty G, Clemens TL. Tsc2 is a molecular checkpoint controlling osteoblast development and glucose homeostasisMol Cell Biol., 2014; 34:1850-62
  3. Frey JL, Li Z, Ellis JM, Zhang Q, Farber CR, Aja S, Wolfgang MJ, Clemens TL, Riddle RC. Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblastMol Cell Biol., 2015. 1343-14
  4. Li Z, Frey JL, Wong GW, Faugere MC, Wolfgang MJ, Kim JK, Riddle RC, Clemens TL. Glucose Transporter-4 Facilitates Insulin-Stimulated Glucose Uptake in OsteoblastsEndocrinology, 2016; 157:4094-4103
 

Research Team

  • portrait of Thomas Clemens Thomas Clemens is the Lewis Cass Spencer professor of orthopaedic surgery and the vice chair for research in the Department of Orthopaedic Surgery at Johns Hopkins. Dr. Clemens received his Ph.D. in Biochemistry from the University of London and completed postdoctoral training as a research fellow in medicine at Massachusetts General Hospital. Dr. Clemens was an associate professor in medicine at Cedars-Sinai Medical Center, where he founded a master’s program in biomedical sciences. Subsequently, he was a professor of medicine at the University of Cincinnati, where he directed the Pathobiology and Molecular Medicine graduate program.

    In 2004, Dr. Clemens became director of the Division of Molecular and Cellular Pathology at the University of Alabama at Birmingham, where he established a Howard Hughes Medical Institute-funded Med into Grad doctoral program.

    Dr. Clemens’ research is focused on identification of the cellular and molecular mechanisms, which control bone osteoblast activity. He has authored more than 150 original publications, and has published a number of book chapters. He has served as a council member of the American Society for Bone and Mineral Research and was the program co-chair for the 2002 national meeting. He is the immediate past editor-in-chief of the Journal of Bone and Mineral Research.

  • headshot of Naomi DirckxNaomi Dirckx, Ph.D., completed her Ph.D. at KU Leuven in Belgium where she investigated the role of the skeleton in global glucose homeostasis by focusing on hypoxia signaling in the osteoblast.

    Currently, she is a 3rd year postdoctoral fellow in the lab of Thomas Clemens, Department of Orthopaedic surgery. Her current research aims to discover the role of citrate in bone strength and quality and to unravel the metabolic pathways by which osteoblasts generate citrate and incorporate it in the minerals. A better understanding of how this critical metabolic substrate impacts bone mineralization is immediately relevant to developing better strategies for improving bone quality in metabolic diseases such as osteoporosis and diabetes. Naomi is postdoc representative of the Department of Orthopaedic Surgery and board member of the Johns Hopkins Postdoctoral Association (JHPDA).

  • portrait of Zhu LiDr. Zhu Li received his M.D. degree at Dalian Medical University in China in 1989.

    Before he joined Thomas Clemens’ lab at Johns Hopkins University in 2010, Dr. Li worked at other institutions in North America including The University of Chicago, The University of Western Ontario in Canada and the University of Medicine and Dentistry of New Jersey.

    In addition to working on his research projects, Dr. Li is a lab manager — in that role he helps order lab supplies, monitor expenses and budgets, manage the day-to-day running of the lab, and assure laboratory compliance with regulatory requirements and Johns Hopkins University standards, policies and procedures.

    “My work concerns the role of sensory nerves in skeletal repair. In order to determine the requirement of NGF-dependent TrkA sensory nerves in bone repair, we use a well-characterized mouse model of nondisplaced, stress fracture by damaging forelimb compression to determine the cellular source(s) of NGF and its spatial and temporal relationship to TrkA sensory re-innervation of bone using Thy1-YFP and NGF-eGFP reporter mice and TrkA genetic models.” 

  • portrait of Robert TowerOriginally from Canada, Dr. Robert Tower earned his Ph.D. in the department of Radiology and Neuroradiology at the Christian-Albrecht University of Kiel in Northern Germany where he used the favorable bone targeting properties of bisphosphonates to develop new in vivo imaging approaches and targeted anti-tumor therapeutics.

    Prior to joining the Clemens lab in June, 2019, Dr. Tower worked at KU Leuven in Belgium, as well as the University of Pennsylvania to understand the role of the vasculature in bone development, homeostasis and repair. Currently, Dr. Tower works on the role of sensory innervation in the bone. This project makes use of in vitro microfluidics, culturing bone marrow stromal cells (BMSCs) and primary neurons isolated from dorsal root ganglia, Thy1-YFP and NGF-GFP reporter mice, and a transgenic model of TrkA sensory nerve disruption. Using wholemount sections and confocal imaging, as well as single-cell sequencing and spatial transcriptomics, this project aims to unravel the role of sensory innervation in the bone during development and homeostasis, as well as the neural-derived factors responsible for these effects.

  • portrait of Qian ZhangQian Zhang received her Ph.D. in biochemistry and molecular biology from the Institute for Nutritional Sciences, Chinese Academy of Sciences.

    "Patients with obesity and type 2 diabetes have an increased risk of bone fractures. Recent studies have shown that bone cells produce endocrine factors that can regulate both bone remodeling and energy metabolism. In my study, I am using knockout mice to identify the role of these factors in regulating bone and energy metabolism. My studies should help to clarify the communication of bone and other metabolic tissues."

 

Alumni

  • Angela R. VerardoEducation: M.D., New York Medical College, 2012 B.S., Northeastern University, 2007.
    Fellowship: Pediatric Endocrinology, Johns Hopkins University School of Medicine, 2018
    Research and Clinical Interests: Environmental microbiology, circadian rhythms, bioenergetics of the osteoblast
  • Zhi LiEducation: Ph.D., Shanghai Brain Research Institute, Chinese Academy of Sciences.
    Research and Clinical Interests: His research focuses on the characterization of the mechanism by which the peripheral nervous system regulates bone development and repair.
  • Ryan TomlinsonEducation: Ph.D., Biomedical Engineering, Washington University in St. Louis, 2013. B.S.E., Biomedical Engineering, Case Western Reserve University, 2008.
    Fellowship: Orthopaedic Surgery, Johns Hopkins University, 2016
    University Appointment: Assistant Professor, Johns Hopkins Department of Orthopaedic Surgery, 2016
    Research and Clinical Interests: Sensory nerves in bone, fracture repair, and skeletal mechanobiology
  • Doug DiGirolamoEducation: Ph.D., The University of Alabama, 2008. B.S., Pennsylvania State University, 2001.
    University Appointment: Assistant Professor, Johns Hopkins Department of Orthopaedic Surgery, 2009
    Research and Clinical Interests: Dr. DiGirolamo’s research interests include musculoskeletal biology — in particular, studying the pathways that enable the communication between bone and skeletal muscle that is necessary for them to coordinate their development and mass. Dr. DiGirolamo's prior research interests included the roles of GH and IGF-1 signaling in skeletal development, breast-cancer bone metastasis and cancer angiogenesis.
    He is affiliated with the American Society for Bone and Mineral Research and the Endocrine Society, and has served as the administrative editor of the Journal of Bone and Mineral Research.
  • Ryan RiddleEducation: Ph.D., Pennsylvania State University, 2007. B.S., Loyola University Maryland, 2002.
    Fellowship: The University of Alabama at Birmingham, 2007
    University Appointment: Associate Professor, Johns Hopkins Department of Orthopaedic Surgery, 2017
    Research and Clinical Interests: Sensory nerves in bone, fracture repair and skeletal mechanobiology
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