NICHD Osteogenesis Imperfecta Research Information

NICHD conducts research on osteogenesis imperfecta in order to clarify the ways in which the primary gene defect causes skeletal fragility and other connective-tissue symptoms. The institute also aims to apply this knowledge to the treatment of children with these conditions.

Following the discovery of the genetic source of recessive OI, NICHD researchers now are working to advance understanding of its cellular and biochemical mechanisms. Parallel to this are studies with mouse models for OI to study disease pathogenesis and the skeletal matrix of OI, the effects of pharmacological therapies, and approaches to gene therapy.

Clinical studies are also a significant piece of NICHD’s OI research effort. In particular, these focus on children with types II and IV OI.

Through its intramural and extramural organizational units, the NICHD conducts and supports research on OI.

• Institute Activities and Advances
• Other Activities and Advances

Institute Activities and Advances

Medications for OI

NICHD researchers from the Section on Heritable Disorders of Bone and Extracellular Matrix are conducting clinical studies of a bisphosphonate drug called pamidronate 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 whether bone mineral density is improved and determine whether there are changes in motor function, muscle strength, or bone pain.¹

NICHD researchers are exploring additional therapies for treating OI, including medications that build bone mass. One potential treatment, sclerostin antibody (Scl-Ab) therapy, improved bone mass in mice.²

In a recent study using a mouse model for OI generated at the NICHD, researchers and their colleagues characterized the differentiation of bone marrow stem cells in adult mice into other cell types. They found that the ability of the stem cells to turn into bone cells was impaired, shunting the precursor cells into the pathway to become fat cells. Researchers then treated the OI mouse model with bortezomib (Btz), which the Food and Drug Administration has approved for treating a cancer (myeloma) that begins in certain bone marrow cells. Treating the OI mouse model with Btz improved the capacity for bone marrow stem cells to turn into bone cells and improved whole bone properties. Although Btz itself is not a suitable therapy for OI, given these study findings, future research may target bone marrow stem cells as an approach to treat OI.³

Bone Marrow Transplants for OI

Over the past several years, NICHD researchers from the Section of Physical Biochemistry (SPB) and the Section on Heritable Disorders of Bone and Extracellular Matrix, 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.^4,5,6 These studies, as well as gene therapy studies, may one day lead to treatments for OI.

Natural History of OI

Section on Heritable Disorders of Bone and Extracellular Matrix 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.⁷

Studies of Recessive OI

NICHD researchers have discovered three of the known genes that cause recessive OI. Recessive OI is caused by mutations 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 Congenital Anomalies 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.⁸

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.⁵

In 2010, NICHD researchers in the Section on Heritable Disorders of Bone and Extracellular Matrix  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.

Recently, Section on Heritable Disorders of Bone and Extracellular Matrix researchers and their colleagues conducted a study to determine the prevalence of one of these recessive OI mutations among Mid-Atlantic African Americans, African immigrants, West Africans, and Africans from areas beyond West Africa. The mutation is in the LEPRE1 gene, which codes for a protein known as P3H1 that is part of the collagen-folding complex. The investigators screened DNA from the target populations and estimated that 0.4% of Mid-Atlantic African Americans carry the genetic mutation, affecting 1 in 260,000 births. The prevalence is higher in West Africa—1.48% of people in Nigeria and Ghana carry the genetic mutation, affecting 1 in 18,260 births. The researchers estimated that the mutation originated between 650 and 900 years ago in this part of West Africa (they did not find it in neighboring countries). Taken together, these findings suggest that the mutation for this type of recessive OI was introduced to populations in the United States during the Atlantic slave trade.⁹

Other Activities and Advances

OI Mutation Consortium

The Section on Heritable Disorders of Bone and Extracellular Matrix 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.⁵