HomeENGLISH MAGAZINEOsteoporosis in the core: bone GWAS enlenghtens the growING 3

Osteoporosis in the core: bone GWAS enlenghtens the growING 3

Osteoporosis is a common chronic form of disability due to loss of bone mineral density (BMD) and changes in bone architecture and bone material properties eventually lead to a high fracture rate. During their life, women lose 30-50% of their peak bone mass, while men lose 20-30%. The risk of fracture is higher in individuals with lower BMD. Over the age of 50, many women of European origin will suffer at least one fracture; of these, many are at high risk of a subsequent fracture. The subsequent loss of mobility and the increase in mortality have an enormous financial impact estimated at 17 billion dollars a year, and will probably increase in the coming decades due to the aging of the population. BMD is a classic complex trait influenced by behavioral, environmental and genetic factors. There is strong evidence of genetic predisposition to osteoporosis, estimated to be roughly 70%. The differences in ancestry of the population also reflect the genetic component.

Scientists have exploited powerful data analysis tools and three-dimensional studies of genomic geography, to implicate new risk genes for osteoporosis, the chronic bone-weakening condition that affects millions of people. Knowing the causal genes can later open the door to more effective treatments. Struan Grant, PhD, director of the Center for Spatial and Functional Genomics (CSFG) at the Children’s Hospital of Philadelphia and his team identified two new genes that affect bone-forming cells related to fractures and osteoporosis. Furthermore, the research methods they used could be applied more broadly to other diseases with a genetic component. He co-directed the study with Andrew D. Wells, PhD, and Kurt D. Hankenson, PhD, an expert in bone formation and remodeling at the University of Michigan. The genetic researcher Alessandra Chesi, PhD, also from Philadelphia Hospital, was the first author, along with three other joint authors.

The study group studied genetic loci, or DNA regions, previously established to be associated with bone mineral density in genome-wide association studies (GWAS), both in adults and in children. Scientists have long known that the gene closest to a variant associated with a disease is not necessarily the cause of the disease. Since the GWAS research detects single-base changes in DNA that are not usually found in obvious parts of the genome, much research has turned to the broader context of interactions within the genome. Sometimes the changes, called single-nucleotide polymorphisms or SNPs, found in GWAS are found near a culprit gene. Most often the signal comes from a non-coding region of DNA that regulates another gene that could be thousands of bases away from the DNA sequence. The geography of the genome is not linear. Since DNA is folded into chromosomes, parts of the genome can make physical contact, allowing key biological interactions that influence the way a gene is expressed.

Analyzing how chromatin is organized in specific forms, spatial genomics offers a view of how genes physically interact with the regulatory regions of DNA that initiate transcription. Researchers used advanced high-resolution tools to analyze the interactions of the entire genome in human osteoblasts, the bone-forming cells. Their analytical tools use a “multi-omic” approach, integrating genome sequence data and details of chromatin structure, to map interactions between potential gene promoters related to BMD and regions that host genetic variants related to BMD biology. The study identified two new genes, ING3 and EPDR1, which in turn revealed strong effects on human osteoblasts. While researchers do not rule out other possible causal genes, the ING3 gene was particularly distinguished because they found that the genetic signal in this region was the strongest associated with wrist bone density – the main site of fracture in children.Researchers have long known that bone accumulation in childhood can strengthen bone health in adulthood. This new line of research may present strategies for building on that knowledge.

Although current research has not delved into the molecular basis for the regulation of bone formation by ING3 and EPDR1, researchers have some clues from other biological models. Two mechanisms can be proposed from which ING3 influences osteoblast differentiation. First, since the ING3 protein is part of the chromatin remodeling protein complexes (MED/HATs), silencing of ING3 could influence key genes during the differentiation of human osteoblasts. Second, given that ING3 levels are altered in different types of cancer and ING3 interacts with the p53 onco-suppressor network, the absence of ING3 may allow cells to avoid differentiation by continuously returning to the cell cycle. In this way, osteoblastic cells shall never committ toward a genetic maturation program. The team deems that the biological pathways affected by this gene may present targets for therapies to strengthen bone mineral density and ultimately prevent fractures, Alongside, there could be more opportunities for targeted treatments for many different diseases, including some pediatric cancers, diabetes and even autoimmunity.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Chesi A et al. Nat Commun. 2019 Mar; 10(1):1260.

Meng XH, Chen XD et al. Bone. 2018; 113:41-48.

Calabrese GM et al. Cell Syst. 2017 Jan; 4(1):46-59.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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