Opportunities and Challenges in Functional Genomics Research in Osteoporosis: Report From a Workshop Held by the Causes Working Group of the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society on October 5th 2020

Abstract

The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by “multi-omics” database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the “osteocyte signature”, by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.

Novel Nanohydroxyapatite (nHAp)-Based Scaffold Doped with Iron Oxide Nanoparticles (IO), Functionalized with Small Non-Coding RNA (miR-21/124) Modulates Expression of Runt-Related Transcriptional Factor 2 and Osteopontin, Promoting Regeneration of Osteoporotic Bone in Bilateral Cranial Defects in a Senescence-Accelerated Mouse Model (SAM/P6). PART 2

“…Worldwide, OP each year contributes to >8.9 million fractures, of which most occur in Europe. 1,2 The advancement in the field of osteoporosis treatment and prevention is undeniable, however, bone fracture regeneration in osteoporotic/geriatric patients is still problematic, hence requires novel therapeutic strategies. [3][4][5] At the molecular level, the disease is triggered by an imbalance between the activity of bone-forming and resorbing cells.…”

The role of genetic and epigenetic factors in determining the risk of spinal fragility fractures: new insights in the management of spinal osteoporosis

“…In terms of potential future directions of research, there is a current pertinent needed for an integrated multi-omics approach that can bring together the various advances from imaging and (epi)genomics that we have highlighted in order to generate a practical tool for clinicians to improve management and outcomes for patients ( 11 , 53 , 79 ). The benefit of this would be two-fold; first it can decrease the necessity for duplicating research efforts, and secondly it would bring together what are at present a complex interplay of various factors.…”

CD137 Regulates Bone Loss via the p53 Wnt/β-Catenin Signaling Pathways in Aged Mice

“…Molecular pathways and genes interact to cause senile osteoporosis, which is a complicated, multifactorial disease ( 27 , 28 ). In the present study,241 DEGs were analyzed and screened from 3 gene expression profiles (GSE35956, GSE35957, and GSE35959) containing osteoporosis and normal tissue samples.…”