A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

Formosa M et al. Front. Endocrinol., 13 August 2021
REVIEW article

Front. Endocrinol., 13 August 2021 | https://doi.org/10.3389/fendo.2021.709711

Melissa M. Formosa1,2Dylan J. M. Bergen3,4Celia L. Gregson4Antonio Maurizi5Anders Kämpe6,7Natalia Garcia-Giralt8Wei Zhou9Daniel Grinberg10Diana Ovejero Crespo8M. Carola Zillikens9Graham R. Williams11J. H. Duncan Bassett11Maria Luisa Brandi12Luca Sangiorgi13Susanna Balcells10Wolfgang Högler14,15Wim Van Hul16 and Outi Mäkitie17,18,19* on behalf of GEMSTONE Working Group 3 COST Action

  • 1Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
  • 2Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
  • 3School of Physiology, Pharmacology, and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom
  • 4The Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, United Kingdom
  • 5Department of Applied Clinical Sciences and Biotechnological, University of L’Aquila, L’Aquila, Italy
  • 6Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 7Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  • 8IMIM (Hospital del Mar Research Institute), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Barcelona, Spain
  • 9Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
  • 10Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain
  • 11Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
  • 12Department of Surgery and Translational Medicine (M.L.B.), University of Florence, Florence, Italy
  • 13Department of Medical Genetics and Skeletal Rare Diseases, IRCCS Rizzoli Orthopaedic Institute, Bologna, Italy
  • 14Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria
  • 15Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
  • 16Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
  • 17Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 18Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
  • 19Folkhälsan Research Centre, Folkhälsan Institute of Genetics, Helsinki, Finland


Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.

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