Osteogenesis Imperfecta: Research Activities and Scientific Advances

Through its intramural and extramural organizational units, the NICHD conducts and supports research on osteogenesis imperfecta. NICHD researchers have discovered all three of the known genes that cause recessive OI.

In 2010, NICHD investigators discovered the third gene that accounts for cases of recessive OI. The gene codes for a protein called cyclophilin B, which is involved in folding collagen into its final shape.

• Institute Activities and Advances
• Other Activities and Advances

Institute Activities and Advances

Bisphosphonate Clinical Trials

NICHD researchers from the Bone and Extracellular Matrix Branch (BEMB) are conducting clinical studies of a bisphosphonate drug called pamidronate (pronounced pam-id-ROH-neyt) in children who have type III or type IV OI. The studies will compare different doses of the drug by itself or in combination with growth hormone. The aim is to test bone mineral density as well as improvements to function and muscle strength and decreases in pain.¹

Bone Marrow Transplants for OI

Over the past several years, NICHD researchers from the Section of Physical Biochemistry (SPB) and BEMB, along with university colleagues, have suggested that transplanting healthy bone marrow into mice with OI may someday lead to an effective treatment for people.

In 2009, a group published the results of a study in which bone marrow was transplanted in utero to mice with lethal OI mutations. About 2% of the transplanted cells remained after birth. These cells produced normal collagen, which accounted for about 20% of all type I collagen in the mice. About 3 in 10 mice not only survived birth but also had only mild OI symptoms.^2,3,4These studies, as well as gene therapy studies, may one day lead to treatments for OI.

Long-Term Study

BEMB researchers are recruiting patients for a long-term study of types III and IV OI from birth to age 25. They aim to assess the natural history of the disease, including any symptoms that affect the teeth, heart, lungs, brain, and hearing. Heart and lung problems are a major cause of disability and death in adults with OI, but it’s not known how these complications develop or whether susceptible people can be identified early in childhood. The study also will include research on the genetics of OI; participants and their parents will be tested for OI gene mutations.⁵

Studies of Recessive OI

Recessive OI is caused by mutatons in genes that code for parts of a protein complex. The complex folds and shapes collagen before it is sent out of a cell. Researchers supported by the NICHD’s Developmental Biology and Structural Variation Branch are using human tissues and novel mouse models to better understand how recessive OI comes about and how to distinguish it from the more common dominant OI.⁶

NICHD researchers in the SPB are focusing on how specific recessive mutations affect the shape of the collagen protein. They have found that mutations that affect a section of collagen called the “N-anchor” result in the loose joints that are common in people with OI. Mutations that affect another section, called the “C-anchor,” seem to result in lethal OI. The group also is studying how protein folding goes awry in recessive OI, and how the stress of improper folding affects the body’s bone-forming cells.³

In 2010, NICHD researchers in the BEMB found a new mutation that is responsible for some recessive forms of OI. The newly identified mutation is in the gene that contains the information needed to make the protein Cyclophilin B. This protein is part of a complex of three proteins that modifies collagen, folding it into a precise molecular configuration, before it is secreted from cells.

Other Activities and Advances

Osteogenesis Imperfecta Mutation Consortium

The BEMB leads an international consortium of connective tissue laboratories that compile and analyze information on mutations in type I collagen. The first analysis of the consortium’s database, published in 2007, listed more than 830 mutations. The database now contains more than 1,570 mutations from nine international laboratories.⁴

1. NIH. (2012). Pamidronate to treat osteogenesis imperfecta in children. Retrieved May 7, 2012, from http://clinicaltrials.gov/ct2/show/NCT00005901 [top]
2. Panaroni, C., Gioia, R., Lupi, A., Besio, R., Goldstein, S. A., Kreider, J., et al. (2009). In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model of classical, dominant osteogenesis imperfecta. Blood, 114, 459–468. [top]
3. NICHD. (2011).2011 Annual report of the Division of Intramural Research. Retrieved May 7, 2012, from http://annualreport.nichd.nih.gov/spb2.html [top]
4. NICHD. (2011). 2011 Annual report of the Division of Intramural Research. Retrieved May 7, 2012, from http://2011annualreport.nichd.nih.gov/bemb.html [top]
5. NIH. (2012). Evaluation and intervention for the effects of osteogenesis imperfecta. Retrieved May 7, 2012, from http://clinicaltrials.gov/ct2/show/NCT00001594 [top]
6. Research Portfolio Online Reporting Tools. (n.d.). Pathogenesis of novel forms of osteogenesis imperfecta (project information 1P01HD070394-01). Retrieved May 7, 2012, from http://projectreporter.nih.gov/project_info_description.cfm?aid=8196080&icde=11963151 [top]