Mutations in WNT1 prompt bone disease in children and adults
Mutations in the gene WNT1 are associated with both early-onset osteoporosis and the brittle bone disease osteogenesis imperfecta, a finding that can help answer long-held questions about the disorders and prompt new explorations in the clinic and laboratory, said an international consortium of researchers led by those at Baylor College of Medicine in a report in the New England Journal of Medicine.
"This finding brings up important questions for further research," said Dr. Brendan Lee, professor of molecular and human genetics at BCM and corresponding author of the report. "What happens if you make higher levels of the protein associated with WNT1? Can you use this protein as a biomarker in blood for the status of bone formation?"
Lee and his colleagues came to this study with a long history of studying diseases that result in brittle bones. They and others have known for a long time that most families with children who had the genetic brittle bone disease osteogenesis imperfecta (OI) often carry mutations in type I collagen, the most abundant protein in bone.
However, in 2006, their work on families with unknown causes of brittle bone diseases led to the discovery of the first new genes for the disease in over two decades. This has since led to a string of discoveries by them and others on how genes in connective tissues control bone growth. In this, perhaps their most surprising discovery, they found mutations in the WNT1 gene in children with osteogenesis imperfecta. WNT signaling plays a central role in much of development, including bone growth, but there are 19 WNT proteins in humans. The search for a better understanding of the disease and the gene mutation in these children has now led to the identification of at least one key WNT protein that controls bone growth.
"Now, 20 years later, we know the identity of at least one essential WNT ligand important in human bone formation," said Lee, also a Howard Hughes Medical Institute investigator.
This work has broader implications. In this collaboration with Lee’s group, Dr. Outie Maikite, a endocrinologist in Finland, identified a large Finnish family with severe early-onset osteoporosis (a condition in which the density and quality of bone is reduced – something usually associated with age and menopause) in whom affected members carried one mutated copy of the WNT1 gene. Together, the genetic evidence suggests that the strength of the bone is exquisitely sensitive to the dose of WNT1 protein.
"When there is a mutation in only one copy of the gene, the person develops osteoporosis at an early age," said Lee. "When both copies are affected, the person has osteogenesis imperfecta."
Studies in the laboratory confirmed that the mutations adversely affected WNT signaling and the ability of bone cells to develop and make minerals. Another surprising finding was that WNT1 was not made primarily by the osteoblast –the primary bone forming cells that line the surface of bone. Instead it was made by others cells deeply embedded within bone called the osteocyte, and also by cells of the immune system, the B cell.
While it had been known that WNT signaling played an important role in bone formation, targeting it with a drug or chemical was difficult. On the other hand, the protein associated with WNT1 exists outside the cell and tissue and is easier to affect with a drug.
"This is another target for treatment of osteoporosis," said Lee. The dominant therapies for osteoporosis affect the resorption of old bone. However, newer therapies are seeking to increase the formation of new bone. In fact, some of thse approaches target WNT signaling pathways.
Others who took part in this work include Kyu Sang Joeng, PhD; Philippe M. Campeau, MD; Monica Grover, MD; James T. Lu, B.S., and Richard A. Gibbs, PhD, all of BCM; Christine M. Laine, MD; Minna Pekkinen, PhD; Maija Wessman, PhD; Mira Aronen; Anna-Elina Lehesjoki, MD PhD, and Outi Mäkitie, MD, PhD; all of Folkhälsan Institute of Genetics in Helsinki, Finland; Riku Kiviranta, MD PhD; Kati Tarkkonen, PhD; Terhi J. Heino, PhD, and Vappu Nieminen-Pihala, MSc, all of University of Turku, Turku, Finland; Tero Laine, MD PhD, Sahlgrenska University Hospital, Gothenburg, Sweden; Heikki Kröger, MD, PhD of University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; William G. Cole, MD PhD of University of Alberta, Edmonton, Canada; Lisette Nevarez, B.S., Deborah Krakow, MD, and Daniel H. Cohn, PhD, all of University of California Los Angeles and Cynthia J.R. Curry, MD, of University of California San Francisco.
Funding for this work came from the Folkhälsan Research Foundation; the Academy of Finland; the Sigrid Juselius Foundation; the Foundation for Pediatric Research; the Waldemar von Frenckell Foundation; the Helsinki University Research Funds, Helsinki, Finland; the European Calcified Tissue Society Career Establishment Award; National Institutes of Health (Grants PO1 HD22657, PO1 HD070394); Canadian Institutes of Health Research clinician-scientist training award; the Rolanette and Berdon Lawrence Bone Disease Program of Texas; and the NIH National Research Service Award (Fellowship F32 AR063616).