Pathophysiology of Skeletal Disease
File(s)
Author(s)
Williams, Graham Richard
Type
Thesis
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).
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).
Version
Open Access
Date Issued
2022-01
Date Awarded
2023-04
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Science (DSc)