Baylor College of Medicine researchers have found a new target for treating osteogenesis imperfecta, more commonly known as brittle bone disease. Dr. Brendan Lee, a professor at Baylor and a Howard Hughes Medical Institute investigator, was the principal investigator of the study recently published in Nature Medicine. “There are many genetic causes of brittle bone disease in children and adults,” said Dr. Lee in a press release. “We have discovered many of them but clinicians still cannot easily distinguish the different forms.”
Osteogenesis imperfecta (OI) comes in two forms: dominant OI and recessive OI. In dominant OI, type I collagen is structurally mutated, and in recessive OI, type I collagen post-translational modification is erroneous. Using two mouse models representing the two forms of OI, the team of scientists discovered excessive transforming growth factor-beta (TGF-β) signaling to be common to both forms. “This identified an important concept in bone disease that while many different genetic mutations can affect the proteins in the bone matrix (like collagen) they act in a common pathway to cause the bone disease – that is they affect how signaling proteins called TGF-β are delivered to cells in the bone,” said Dr. Lee.
Collagen and TGF-β are related because collagen fibrils associate with TGF-β in the extracellular matrix. This sequesters TGF-β, affecting its bioactivity for regulating osteoblast bone formation. In the mouse models, reduced binding of TGF-β to collagen via the linker molecule decorin resulted in excessive TGF-β signaling and poor bone integrity. “We now have a deeper understanding for how genetic mutations that affect collagen and collagen processing enzymes cause weak bones,” commented Dr. Lee.
By administering the anti-TGF-β neutralizing antibody 1D11, the researchers were able to correct the bone phenotype in both forms of OI. “This treatment appears even more effective than other existing approaches,” concluded Dr. Lee. Unrelated treatments for blocking the TGF-β pathway are currently being developed, so this new research has the potential for being translated into human studies. Additionally, more patients than just those affected by OI may be able to benefit. “We hope this approach will also be useful in more common forms of osteoporosis,” explained Dr. Lee.
The work was a collaboration of a number of authors: Ingo Grafe, Tao Yang, Stefanie Alexander, Erica Homan, Caressa Lietman, Ming Ming Jiang, Terry Bertin, Elda Munivez, Yuqing Chen, Brian Dawson, all of Baylor; Yoshihiro Ishikawa and Hans Peter Bächinger of Oregon Health and Science University in Portland, Mary Ann Weis and David Eyre of the University of Washington in Seattle; T Kuber Sampath of the Genzyme Research Center in Massachusetts and Catherine Ambrose of the University of Texas Health Science Center at Houston all contributed to the research.