High bone mass disorders:​ new insights from connecting the clinic and the bench

Bergen, Dylan J. M.<sup>1,2</sup>; Maurizi, Antonio<sup>3</sup>; Formosa, Melissa M.<sup>4,5</sup>; McDonald, Georgina L. K.<sup>1</sup>; El-Gazzar, Ahmed<sup>6</sup>; Hassan, Neelam<sup>2</sup>; Brandi, Maria-Luisa<sup>7</sup>; Riancho, José A.<sup>8</sup>; Rivadeneira, Fernando<sup>9</sup>; Ntzani, Evangelia<sup>10,11,12</sup>; Duncan, Emma L.<sup>13,14</sup>; Gregson, Celia L.<sup>2</sup>; Kiel, Douglas P.<sup>15</sup>; Zillikens, M. Carola<sup>9</sup>; Sangiorgi, Luca<sup>16</sup>; Högler, Wolfgang<sup>6,17</sup>; Duran, Ivan<sup>18</sup>; Mäkitie, Outi<sup>19,20,21</sup>; Van Hul, Wim<sup>22</sup>; Hendrickx, Gretl<sup>23</sup>

Affiliations

¹School of Physiology, Pharmacology, and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK

²Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, UK

³Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

⁴Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta

⁵Center for Molecular Medicine and Biobanking, University of Malta, Msida, Malta

⁶Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria

⁷Italian Bone Disease Research Foundation (FIRMO), Florence, Italy

⁸Department of Internal Medicine, Hospital U M Valdecilla, University of Cantabria, IDIVAL, Santander, Spain

⁹Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

¹⁰Department of Hygiene and Epidemiology, Medical School, University of Ioannina, Ioannina, Greece

¹¹Center for Evidence Synthesis in Health, Policy and Practice, Center for Research Synthesis in Health, School of Public Health, Brown University, Providence, RI, USA

¹²Institute of Biosciences, University Research Center of loannina, University of Ioannina, Ioannina, Greece

¹³Department of Twin Research & Genetic Epidemiology, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK

¹⁴Department of Endocrinology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

¹⁵Marcus Institute for Aging Research, Hebrew SeniorLife and Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School, Broad Institute of MIT & Harvard, Cambridge, MA, USA

¹⁶Department of Rare Skeletal Diseases, IRCCS Rizzoli Orthopaedic Institute, Bologna, Italy

¹⁷Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

¹⁸University of Malaga, Malaga, Spain

¹⁹Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

²⁰Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland

²¹Folkhälsan Research Centre, Folkhälsan Institute of Genetics, Helsinki, Finland

²²Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

²³Department of Human Genetics, KU Leuven, Leuven, Belgium

Abstract and keywords

Monogenic high bone mass (HBM) disorders are characterized by an increased amount of bone in general, or at specific sites in the skeleton. Here, we describe 59 HBM disorders with 50 known disease-causing genes from the literature, and we provide an overview of the signaling pathways and mechanisms involved in the pathogenesis of these disorders. Based on this, we classify the known HBM genes into HBM (sub)groups according to uniform Gene Ontology (GO) terminology. This classification system may aid in hypothesis generation, for both wet lab experimental design and clinical genetic screening strategies. We discuss how functional genomics can shape discovery of novel HBM genes and/or mechanisms in the future, through implementation of omics assessments in existing and future model systems. Finally, we address strategies to improve gene identification in unsolved HBM cases and highlight the importance for cross-laboratory collaborations encompassing multidisciplinary efforts to transfer knowledge generated at the bench to the clinic.

Keywords: DISEASES AND DISORDERS OF/RELATED TO BONE; ANABOLICS; THERAPEUTICS; GENETIC ANIMAL MODELS; ANIMAL MODELS; CELL/TISSUE SIGNALING; PARACRINE PATHWAYS; GENETIC RESEARCH

Links

DOI: 10.1002/jbmr.4715

PubMed: 36161343

WoS: 000870692100001

History

Received: 2022-05-25

Revised: 2022-09-05

Accepted: 2022-09-22

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