Pathophysiology of Skeletal Disease

Abstract

These studies have resulted in substantial advances in the field of osteoporosis and osteoarthritis research. Crucial contributions to pivotal osteoporosis GWAS identified 518 bone mineral density and 13 fracture loci that now account for over 20% of the population variance in bone density. We identified over 300 novel eBMD loci and validated numerous genes, including (i) transferrin receptor-2 as a novel regulator of bone mass acting via BMP/p38MAPK/Wnt signalling, (ii) over 100 genes that determine bone mass, quality and strength comprising enzymes, ion and amino acid transporters, cell cycle regulators, transcription factors and modulators of non-canonical Wnt signalling, and (iii) age-specific and sexually dimorphic genetic effects on bone mineral density. Recent discoveries include (i) identification of a new cell type with a unique transcriptome, termed the “osteomorph”. Bone resorbing multinucleated osteoclasts undergo cycles of cell fission and fusion, recycling via osteomorphs in the bone marrow to regulate osteoclast motility and dynamic bone remodelling in vivo, (ii) elucidation of a transcriptome map of genes expressed in osteocytes, the master regulatory cells in bone. Osteocyte signature genes correlate closely with loci identified in human GWAS and in the nosology of monogenic skeletal disorders, establishing the cellular pathogenesis of various skeletal diseases, and (iii) development of novel imaging methods in osteoarthritis disease models and generation of the first multi ‘omic molecular QTL map of human disease to accelerate causative gene discovery in osteoarthritis. This multidisciplinary and international approach is transformative and has resulted in a comprehensive atlas of human and murine genetic influences on bone and joint disease that offer novel insights into the pathophysiology of osteoporosis and osteoarthritis with exciting opportunities for biomarker discovery and drug development. This body of work has resulted in invitations to contribute seminal chapters in major international textbooks, including (i) Genetics of Bone Biology and Skeletal Disease (2018) and (ii) Osteoporosis (2020), and Plenary Lectures to the (i) 21st World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (IOFESCEO WCO), (ii) ASBMR Bone Turnover Markers Annual Meeting, and (iii) 9th Congress of the Romanian Society of Osteoporosis and Musculoskeletal Diseases (all in 2021). My work was recognised by the European Calcified Tissue Society Steven Boonen Clinical Research Award (2018), and I was elected Fellow of the Academy of Medical Sciences (2019), Member of Academia Europaea (2021) and Fellow of the Association of Physicians of Great Britain & Ireland (2021).