Osteogenesis imperfecta, a skeletal disorder caused by mutations in type I collagen, exhibits structural and functional differences on a genotypic level that contribute to diverse phenotypes.
Osteogenesis imperfecta (OI), a skeletal disorder caused by mutations in type I collagen, exhibits structural and functional differences on a genotypic level that contribute to diverse phenotypes.
Brendan Lee, MD, PhD, from the Baylor College of Medicine discussed the genetics of OI and homeostatic mechanisms in the skeleton at the 2014 American Society of Bone and Mineral Research Conference in Houston, Texas.
Human genetics of the skeleton can be analyzed in multiple ways. Scientists can examine phenotype (for example, radiologic evidence in skeletal morphology and bone density), candidate genes (including essential transcription factors and their targets), signaling pathways, and phenotypic expansion (new alleles). Once they understand the genetic underpinnings of skeletal disease, scientists may be able to develop targeted therapy to address diverse phenotypes.
Dr Lee’s lab is examining bone matrix, mineralization, and density in OI. OI ranges in debility from increased vulnerability to fractures to severe disease involving deformity and contractures.
In OI, patients suffer from low bone mass, bone fragility/deformity/fractures, and extra-skeletal manifestations. They exhibit a wide phenotypic spectrum. For example, some OI only involves bone disease, while Bruck syndrome is a type of OI with significant contractures.
This variation brings up questions of how structure and function on a genotypic level contribute to the diverse phenotypes. In one experiment, Dr Lee evaluated the differential contribution of chaperoning. He found that mice deficient in prolyl 3-hydroxylase 1 (P3H1) show decreased trabecular bone mass as well as ligament, tendon, and skin manifestations, suggesting that hydroxylation of this protein is required in tissue.
Brittle bone disease can be caused by abnormalities in cellular trafficking, matrix cell signaling, or matrix collagen cross-linking. In another experiment using a mouse model of OI, Dr Lee studied the overlap of the CRTAP phenotype with increased TGF-beta signaling. He found decreased bone mass, increased bone turnover, and increased osteocyte density. Inhibition of TGF-beta improved trabecular bone mass in the spine, suggesting that anti-TGF-beta may be used as a treatment modality.
Dr Lee said, we now “see a whole spectrum of rare mutations underscoring different mechanisms of disease.” He then described a third experiment that showed that semi-dominant WNT1 mutations were present in early onset osteoporosis and in OI as a dose-response requirement of a very dominant phenotype.
He concluded by noting that we now have a wide variety of treatments for OI, including bisphosphonates for pediatric OI, teriparatide for adult OI with quantitative defects of collagen, and anti-TGF-beta for various other types of OI.
Dr Lee said that there isn’t “one simple thing that explains it” for OI abnormalities. However, just like there is an overlap between OI and osteoporosis, there is a question of how genetic variants contribute to osteoporosis. Individualized treatment of osteoporosis may be the next important step in therapeutic intervention.
ATS 2024: Bridging the Past, Present, and Future of Respiratory Care
May 16th 2024The application of artificial intelligence in medicine is anticipated as a highlight of ATS 2024, with sessions exploring its applications in research, radiological interpretation, and pediatric pulmonology.
Read More
The Importance of Examining and Preventing Atrial Fibrillation
August 29th 2023At this year’s American Society for Preventive Cardiology Congress on CVD Prevention, Emelia J. Benjamin, MD, ScM, delivered the Honorary Fellow Award Lecture, “The Imperative to Focus on the Prevention of Atrial Fibrillation,” as the recipient of this year’s Honorary Fellow of the American Society for Preventive Cardiology award.
Listen
Looking Back on ISPOR 2024: Hot Policy Topics, Welcome Focus on Employers, and More
May 10th 2024Kimberly Westrich, MA, chief strategy officer of the National Pharmaceutical Council, reflects on the most valuable learnings from the 2024 meeting of ISPOR—The Professional Society for Health Economics and Outcomes Research, including lively discussions of the Inflation Reduction Act and workshops on value assessment.
Read More
Promoting Equity in Public Health: Policy, Investment, and Community Engagement Solutions
June 28th 2022On this episode of Managed Care Cast, we speak with Georges C. Benjamin, MD, executive director of the American Public Health Association, on the core takeaways of his keynote session at AHIP 2022 on public health policy and other solutions to promote equitable health and well-being.
Listen
Posters Characterize DMD Caregiver Experiences, Impact of Gene Therapy on Caregiving Demands
May 10th 2024Posters presented at the ISPOR—The Professional Society for Health Economics and Outcomes Research meeting explored Duchenne muscular dystrophy (DMD) caregiver experiences and gene therapy’s impact on work opportunities for caregivers.
Read More
A Focus on Women: AUA Best Posters Highlight Female Athletes, Prenatal Care, and Women in Urology
May 9th 2024Three posters from the American Urological Association (AUA) 2024 Annual Meeting focused on urinary incontinence in female athletes, prenatal care for fetuses with spina bifida in California, and the experiences of women residents at the Brady Urological Institute.
Read More