Osteogenesis imperfecta (OI) is a debilitating genetic osteodysplasia that results in low bone mass, bone deformity, and bone fractures. Despite extensive research, the molecular pathogenesis behind OI is still poorly understood. Most cases of OI are caused by mutations in the structural protein type I collagen (dominant OI) or in protein complexes that post-translationally modify type I collagen (recessive OI); both types of mutations often lead to biochemical overmodification. Type I collagen, while important for structural integrity of bone is also essential for extracellular matrix (ECM) cell signaling. It extensively interacts with ECM components that regulate bioavailability of signaling molecules, thereby affecting tissue-specific cell behavior. We have demonstrated that excessive activation of the transforming growth factor-beta (TGF?) signaling pathway is pathogenic in mouse models of dominant (Col1?2tm1.1Mcbr) and recessive (Crtap-/-) OI. However, the mechanism by which altered collagen structure or post-translational modification leads to altered signaling in OI is unclear. Small leucine-rich proteoglycans (SLRPs) are important regulators of matrix signaling that also bind type I collagen and could establish a link between structural proteins and signaling. Currently, the SLRPs decorin (Dcn), biglycan (Bgn), and asporin (Aspn) are the only matrix components known to bind both type I collagen and TGF?. Their importance in bone is demonstrated by the phenotype in their absence. The Bgn- knockout mouse has an osteoporosis phenotype with altered sequestration and signaling of TGF? in bone. Only one paper has studied the bone from Dcn-/- mice, but Dcn-knockdown osteoblast cells transplanted into mice generate immature, highly mineralized bone reminiscent of bone from OI patients. Decorin and biglycan from human OI bone samples are produced and secreted in a fetal-like form suggesting a connection between OI and changes in SLRPs. We hypothesize that changes in type I collagen in OI disturb binding to the SLRPs decorin, biglycan, and asporin, which in turn alters TGF? availability in the matrix.
We aim to test this hypothesis by comparing the biochemical interaction of SLRPs with type I collagen from wildtype, dominant OI, or recessive OI mice and determining the effects of SLRPs on TGF? bioavailability and signaling in OI. Our preliminary data implies that decorin binds less to type I collagen from Crtap-/- mutant mice than wildtype mice. Based on this data and the phenotype of Dcn-knockout osteoblasts, the third aim of this project is to characterize the bone phenotype of the Dcn-/- mouse to assess the phenotypic overlap with OI bone. This research is important for establishing common mechanisms of disease, which may provide potential therapeutic targets for patients with dominant or recessive OI.

Public Health Relevance

This project serves to elucidate the role of small leucine-rich proteoglycans (SLRPs) in altered extracellular matrix signaling in the brittle bone disease Osteogenesis Imperfecta (OI). SLRPs provide an important link between structural proteins such as type I collagen and matrix-cell signaling. Through this research we hope to discover novel mechanisms of OI and commonalities that exist between various causes of OI, potentially leading to new targets for therapeutics.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Predoctoral Individual National Research Service Award (F31)
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NIDR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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Baylor College of Medicine
Schools of Medicine
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Grafe, Ingo; Alexander, Stefanie; Yang, Tao et al. (2016) Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta. J Bone Miner Res 31:1030-40