Introduction in Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) literally means "imperfect creation of bones" and hence it is also called as a fragile bone syndrome. Osteogenesis Imperfecta mostly affects the connective tissue in the body and sometimes it also affects tendons, ligaments, eyes, fascia, teeth, ears and skin. This disease is characterized by repeated bone fractures, reduction of bone mass and increase in bone fragility. Hence, Osteogenesis Imperfecta is also termed as "brittle bone disease".

OI is an autosomal dominant disease occurred due to the defects in type I collagen, which is the part of the structure of the extracellular matrix in tendon, skin and bone. The defects are caused when the amino acid glycine is substituted with a bulky amino acid that results in the formation of a bulge in the collagen complex. The wrong structure of collagen is responding in the body by hydrolyzation. If the improper collagen structure is not ruined by the body, then the relationship between the hydroxyapatite crystals and collagen fibrils is changed resulting in the brittle nature of the bone.

The autosomal recessive Osteogenesis Imperfecta cases were also identified in the previous years. The genes associated with the post translational modifications of the type I collagen protein are also involved in causing OI. The autosomal recessive Osteogenesis Imperfecta is caused by the damage of two constituents of the prolyl 3-hydroxylation complex. This defect or damage results in the modification of alpha chain of collagen in ER, prolyl 3-hydroxylase and cartilage-associated protein. There are 8 types of OI.

Around 90 percent of patients with Osteogenesis Imperfecta possess mutations in one type of type I collagen genes COLIA1 and COLIA2. These dominantly inherited mutations are of two types. One is a quantitative defect which results in the synthesis of collagen type I protein in half the normal amounts. Another mutation results in the synthesis of structurally abnormal collagen. In about 10 percent of Osteogenesis Imperfecta patients, mutations in cartilage associated protein or CRTAP without any mutations in COLIA1 and COLIA2 will occur. This condition will lead to excess of post translational modification of type I collagen leading to the delayed folding of the triple helix. The mutations in CRTAP, LEPRE1, PPIB and SER-PINF1 exemplify the recessively inherited OI.

Treatments for Osteogenesis Imperfecta

Several pharmacological agents were used for the treatment of Osteogenesis Imperfecta patients in the past decades. Majority of these agents were able to give good results temporarily and were not effective in many of the controlled trials.

Drug treatment

Bisphosphonates: These are powerful inhibitors of bone resorption reducing the osteoclast number and activity. They also inhibit the remodeling activity of bone repair resulting in enhancing the shape of the vertebrae and mass, increase in cortical width and bone volume, and suppressed turnover of the bone.

Growth hormone: The growth hormone will show a positive effect on bone growth and turnover of bones by triggering the osteoblasts, longitudinal bone growth, triggering the IGF-1 and IGF binding protein-3 expression in osteoblast cultures, collagen metabolism and collagen synthesis. The expression of IGF-1 will regulate the synthesis of type I collagen.

Other agents used for the treatment of Osteogenesis Imperfecta were parathyroid hormone, bortexomib and sclerostin. In cell based treatments used for treating OI, gene targeting therapy and cellular replacement therapy have emerged as promising. Cellular replacement therapy involves the introduction of bone marrow cells into the circulatory system, which contribute to the skeletal tissue. Bone marrow consists of two types of stem cells called mesenchymal (MSCs) and hematopoietic (HSCs) stem cells. MSCs were proved to be capable of directly differentiating into osteogenic cells to treat Osteogenesis Imperfecta in some transplantation studies done in mouse models.

Hematopoeitic stem cell based therapy

Some recent studies have revealed that circulating human osteoblast cells which have the capacity to express osteocalcin and alkaline phosphatase, rise in number at the time of growth during puberty and during fracture restoration. In some studies, it has been identified that cells positive for osteocalcin could create mineral rich nodules, In Vitro and can form bone, In Vivo. This cell population was found to be CD34+, which were derived from hematopoietic stem cells (HSCs). Another vital study showed that the survival and frequency of osteoblast progenitor cells were greater in CD34+ cells than in CD34- cell population of human bone marrow cells.

Many transplantation studies done on mice showed that the transplanted non-adherent BM cells rich in HSCs could generate osteoblasts, In Vivo. In another study, hematopoietic cells and osteoprogenitor cells were transduced with GFP expressing retroviral vector in Osteogenesis Imperfecta mice. The osteopoietic incorporation could exist for just two weeks after transplantation while hematopoieitic engraftment could continue for the total period of the study. Here, the donor derived osteopoiesis was absent due to lack of genetic program or suppression of differentiation of donor stem cells by environmental signals. All these studies have indicated that the progenitor cells for both osteocytic and hematopoietic differentiation were present in non-adherent CD34+, HSC rich bone marrow cells.

Studies carrying out clonal cell transplantation showed that HSCs will also generate non-hematopoietic cells which postulates that the basic defects in Osteogenesis Imperfecta might be present in HSC. This postulation was tested with another experiment where HSCs were transplanted into Osteogenesis Imperfecta mice (oim/oim). HSCs from irradiated EGFP expressing mice were used for transplantation into Osteogenesis Imperfecta mice (oim/oim).

Results of the experiment: At 3, 6 and 9 months of post transplantation of HSCs into mice, improvement in bone architecture was identified through 3D micro-CT images of bones. This improvement was in correlation with the hematopoietic incorporation. The improvement in bone shape accompanied the escalation in trabecular number, bone volume, density and thickness of bone and reduction in trabecular space.


Meenal Mehrotra and Amanda C. LaRue (2013). A Therapeutic Role or Hematopoietic Stem Cells in Osteogenesis Imperfecta, Genetic Disorders, Prof. Maria Puiu (Ed.), ISBN: 978-953-51-0886-3, InTech, DOI: 10.5772/52564. Available from:

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