Bone mineral properties in growing Col1a2+/G610C mice, an animal model of osteogenesis imperfecta

Masci, Marco; Wang, Min; Imbert, Laurianne; Barnes, Aileen M.; Spevak, Lyudmila; Lukashova, Lyudmila; Huang, Yihe; Ma, Yan; Marini, Joan C.; Jacobsen, Christina M.; Warman, Matthew L.; Boskey, Adele L.

doi:10.1016/j.bone.2016.04.011

Cited by 33 publications

(33 citation statements)

References 47 publications

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“…Further, FTIR studies of different OI mouse models with dominant OI mutations (G610C and Mov13) and Lrp5 HBM showed no change in the abnormal mineral to matrix ratio seen in OI bone, consistent with lack of improvement in bone quality. (45, 51) Similar results were seen in another mouse model (Brtl) when juvenile mice were treated for 2 or 5 weeks with Sclerostin antibody. There was no improvement in brittleness nor an effect on the estimated elastic modulus.…”

Section: Osteogenesis Imperfectasupporting

confidence: 72%

Application of anti-Sclerostin therapy in non-osteoporosis disease models

Jacobsen

2017

Bone

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Sclerostin, a known inhibitor of the low density lipoprotein related protein 5 and 6 (LRP5 and LRP6) cell surface signaling receptors, is integral in the maintenance of normal bone mass and strength. Patients with loss of function mutations in SOST or missense mutations in LRP5 that prevent Sclerostin from binding and inhibiting the receptor, have significantly increased bone mass. This observation lead to the development of Sclerostin neutralizing therapies to increase bone mass and strength. Anti-Sclerostin therapy has been shown to be effective at increasing bone density and strength in animal models and patients with osteoporosis. Loss of function of Sost or treatment with a Sclerostin neutralizing antibody improves bone properties in animal models of Osteoporosis Pseudoglioma syndrome (OPPG), likely due to action through the LRP6 receptor, which suggests patients may benefit from these therapies. Sclerostin antibody is effective at improving bone properties in mouse models of Osteogenesis Imperfecta, a genetic disorder of low bone mass and fragility due to type I collagen mutations, in as little as two weeks after initiation of therapy. However, these improvements are due to increases in bone quantity as the quality (brittleness) of bone remains unaffected. Similarly, Sclerostin antibody treatment improves bone density in animal models of other diseases. Sclerostin neutralizing therapies are likely to benefit many patients with genetic disorders of bone, as well as other forms of metabolic bone disease.

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Section: Osteogenesis Imperfectasupporting

confidence: 72%

Application of anti-Sclerostin therapy in non-osteoporosis disease models

Jacobsen

2017

Bone

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Section: Genetic Causes and Mechanisms Of Osteogenesis Imperfectamentioning

confidence: 95%

“…Col1a2 tm1.1Mcbr mice showed reduced bone mass and cortical thickness as well as decreased biomechanical properties [43,44]. In the same study, an increase in mineral-to-collagen ratio was observed, indicating more brittleness in Col1a2 tm1.1Mcbr bones [43,44]. Similar to the Aga2 +/− model, increased expression of Ddit3 and Hsp47 was observed in Col1a2 tm1.1Mcbr mice, indicating that high ER stress and UPR activation may potentially account for osteoblast dysfunction in mutant mice [45].…”

Section: Genetic Causes and Mechanisms Of Osteogenesis Imperfectamentioning

confidence: 99%

Genetic causes and mechanisms of Osteogenesis Imperfecta

Lim

Grafe

Alexander

et al. 2017

Bone

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Osteogenesis Imperfecta (OI) is a genetic disorder characterized by various clinical features including bone deformities, low bone mass, brittle bones, and connective tissue manifestations. The predominant cause of OI is due to mutations in the two genes that encode type I collagen. However, recent advances in sequencing technology has led to the discovery of novel genes that are implicated in recessive and dominant OI. These include genes that regulate the post-translational modification, secretion and processing of type I collagen as well as those required for osteoblast differentiation and bone mineralization. As such, OI has become a spectrum of genetic disorders informing about the determinants of both bone quantity and quality. Here we summarize the known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis. Additionally, we discuss the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression.

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“…Using a Spectrum 300 (Perkin Elmer, CT, USA) infrared spectrometer and microscope, images were acquired at 3 different trabecular and cortical sites for each bone as previously described. (22)…”

Section: Methodsmentioning

confidence: 99%

Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1 +/mov13 mouse model of type I Osteogenesis Imperfecta

Jacobsen

Schwartz

Roberts

et al. 2016

Bone

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Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1+/Mov13) with a high bone mass (HBM) mouse (Lrp5+/p.A214V) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1.

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Bone mineral properties in growing Col1a2+/G610C mice, an animal model of osteogenesis imperfecta

Cited by 33 publications

References 47 publications

Application of anti-Sclerostin therapy in non-osteoporosis disease models

Application of anti-Sclerostin therapy in non-osteoporosis disease models

Genetic causes and mechanisms of Osteogenesis Imperfecta

Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1 +/mov13 mouse model of type I Osteogenesis Imperfecta

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