Osteogenesis Imperfecta: Current and Prospective Therapies

Abstract

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI.

Keywords: gene therapy; iPSCs; mesenchymal stem cells; osteogenesis imperfecta; treatment.

Figure 1

Schematic overview of currently used medications to treat OI. The use of some inhibitors allows for increased bone mass by inhibiting the osteoclast cycle while inducing osteoblasts and osteocytes, e.g., Zoledronate and Pamidronate, the most commonly used BPs with high affinity for hydroxyapatite crystals. In contrast, Romosozumab, which exerts its effect by inhibiting the Wingless-type MMTV integration site family, member 1 (WNT) signalling involved in osteocytes–osteoblasts stimulation, and stimulators, such as growth hormone and teriparatide, induce bone formation instead of inhibiting osteoclast function. Drug names are indicated in italics.

Figure 2

Schematic presentation of somatic cells reprogramming into iPSCs and pluripotency analysis. The generation of iPSCs from fibroblasts and the pluripotency state confirmation are presented. The most commonly used markers of pluripotency are shown. OSKM, Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc); OSLN, Thomson factors (Oct3/4, Sox2, Lin28a, Nanog); iPSCs, induced pluripotent stem cells.

Figure 3

Summary of experimental strategies for OI therapy tested in in vitro, ex vivo, animal models and clinical trials. The promising strategies include (i) the use of Losartan, an angiotensin II-receptor agent with anti-TGF-β properties; (ii) mesenchymal stem cells transplantation as the source of osteoblasts, osteocytes, and chondrocytes; (iii) correction of defective genes, including ODNs, antisense oligodeoxyribonucleotides; siRNA, short interfering RNA; CRISPR–Cas9 and hammerhead ribozymes; (iv) restoring cell homeostasis to improve the severity of the OI phenotype using chemical chaperones, e.g., 4-PBA, 4-phenylbutyrate; (v) iPSCs, induced pluripotent stem cells use.