We and other investigators have demonstrated the importance of LRP5 and LRP6 signaling for affecting bone mass and bone strength in humans and in mice. We now intend to test the hypothesis that enhancing LRP5/6 signaling, to increase bone mass and reduce bone degradation, will be beneficial in mouse models of the human skeletal disorder Osteogenesis Imperfecta (OI). This is high risk, because we may find that increasing bone mass, without fixing the underlying genetic defect, does not increase bone strength or reduce fracture risk in mouse models of OI. This result would be important, since it should temper enthusiasm for testing anabolic therapies that do not address the underlying genetic cause of OI in human patients. HOWEVER, if we find that increasing bone mass also increases bone strength and reduces fracture rates in mouse models of OI, then this would be high impact because it would suggest that anabolic therapies would benefit humans with OI. Nearly 28,000 US citizens have OI. Human OI is clinically and genetically heterogeneous, with most patients (>85%) having mutations in the genes encoding type 1 collagen. Therefore, we will study 3 mouse models of OI, all with type 1 collagen mutations, but with phenotypes that range from mild to severe. This will enable us to determine whether the type of collagen mutation (haploinsufficiency, missense, in-frame deletion) and the severity of the clinical phenotype affect the skeleton's response to enhanced LRP5/6 signaling. We will enhance LRP5/6 signaling in mice by two approaches. In the first approach we will use mice we have already created that have an Lrp5 high bone mass knockin allele (Lrp5HBM). These mice have substantially increased bone mass and bone strength compared to wild-type mice. In the second approach, we will use a mouse monoclonal antibody against SOST, an endogenous LRP5/6 inhibitor. This anti-SOST antibody increased bone mass in mice and in rats, and a humanized version increased bone mass in a primate model and is currently being tested in an FDA approved phase II clinical trial for osteopenia.
Aim 1 involves crossing mice with the Lrp5HBM allele to mice with OI alleles to determine whether the Lrp5HBM allele increases bone mass and bone strength, and reduces fracture rates.
Aim 2 administers the murine anti-SOST monoclonal antibody to OI mice in order to determine whether increasing LRP5 and LRP6 signaling, by inhibiting SOST, increases bone mass and bone strength, and reduces fracture rates in the mouse models of OI. We hope to show that modulating LRP5/6 signaling increases bone mass and bone strength in mouse models of OI. This result would be an important proof of principle to support more detailed studies regarding the optimal timing of therapy in animal models and to look for unexpected deleterious outcomes. Ultimately this knowledge will determine whether modulators of the LRP5/6 signaling pathway, or other therapies that are anabolic in wild-type bone, can be used to improve bone properties in human patients who have OI.
There are nearly 28,000 US citizens who have the skeletal fragility syndrome Osteogenesis Imperfecta (OI). Most patients with OI have mutations in the genes that encode type 1 collagen. These mutations cause an abnormal bone matrix to be produced. The abnormal matrix, itself and the low bone mass that often accompanies it contribute to the patients'skeletal fragility. We want to determine whether increasing bone mass, without correcting the underlying genetic cause of OI, will be sufficient to increase bone strength and reduce the incidence of fractures in animal models of OI. This question is important since drugs are currently available and in clinical trials that do not correct the underlying genetic cause of OI, but which could be used to increase bone mass in humans with OI.
|Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J et al. (2016) Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta. Bone 90:127-32|
|Masci, Marco; Wang, Min; Imbert, Laurianne et al. (2016) Bone mineral properties in growing Col1a2(+/G610C) mice, an animal model of osteogenesis imperfecta. Bone 87:120-9|
|Jacobsen, Christina M; Barber, Lauren A; Ayturk, Ugur M et al. (2014) Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta. J Bone Miner Res 29:2297-306|
|Kedlaya, Rajendra; Veera, Shreya; Horan, Daniel J et al. (2013) Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome. Sci Transl Med 5:211ra158|
|Hann, Steven; Kvenvold, Laura; Newby, Brittney N et al. (2013) A Wisp3 Cre-knockin allele produces efficient recombination in spermatocytes during early prophase of meiosis I. PLoS One 8:e75116|
|Ayturk, Ugur M; Jacobsen, Christina M; Christodoulou, Danos C et al. (2013) An RNA-seq protocol to identify mRNA expression changes in mouse diaphyseal bone: applications in mice with bone property altering Lrp5 mutations. J Bone Miner Res 28:2081-93|