Hindlimb Skeletal Muscle Function and Skeletal Quality and Strength in +/<i>G610C</i>Mice With and Without Weight-Bearing Exercise

Jeong, Youngjae; Carleton, Stephanie M.; Gentry, Bettina A.; Yao, Xiaomei; Ferreira, J. Andries; Salamango, Daniel J.; Weis, MaryAnn; Oestreich, Arin K.; Williams, A. M.; McCray, Marcus G; Eyre, David R.; Brown, Marybeth; Wang, Yong; Phillips, Charlotte L.

doi:10.1002/jbmr.2518

Cited by 22 publications

(34 citation statements)

References 46 publications

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“…We used male mice, even though sexual dimorphism has been observed in wild-type and OI mice 7,14,45,46 . Additionally, we used femurs from the 3-month-old mice and tibiae and vertebrae from the 10-day-old and 2-month-old mice.…”

Section: Discussionmentioning

confidence: 99%

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

Masci

Wang

Imbert

et al. 2016

Bone

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The Col1a2+/G610C knock-in mouse, models osteogenesis imperfecta in a large old order Amish family (OOA) with type IV OI, caused by a G-to-T transversion at nucleotide 2098, which alters the gly-610 codon in the triple-helical domain of the α2(I) chain of type I collagen. Mineral and matrix properties of the long bones and vertebrae of male Col1a2+/G610C and their wild-type controls (Col1a2+/+), were characterized to gain insight into the role of α2-chain collagen mutations in mineralization. Additionally, we examined the rescuability of the composition by sclerostin inhibition initiated by crossing Col1a2+/G610C with an LRP+/A214V high bone mass allele. At age 10-days, vertebrae and tibia showed few alterations by micro-CT or Fourier transform infrared imaging (FTIRI). At 2-months-of-age, Col1a2+/G610C tibias had 13% fewer secondary trabeculae than Col1a2+/+, these were thinner (11%) and more widely spaced (20%) than those of Col1a2+/+ mice. Vertebrae of Col1a2+/G610C mice at 2-months also had lower bone volume fraction (38%), trabecular number (13%), thickness (13%) and connectivity density (32%) compared to Col1a2+/+. The cortical bone of Col1a2+/G610C tibias at 2-months had 3% higher tissue mineral density compared to Col1a2+/+; Col1a2+/G610C vertebrae had lower cortical thickness (29%), bone area (37%) and polar moment of inertia (38%) relative to Col1a2+/+. FTIRI analysis, which provides information on bone chemical composition at ~ 7 µm-spatial resolution, showed tibias at 10-days, did not differ between genotypes. Comparing identical bone types in Col1a2+/G610C to Col1a2+/+ at 2-months-of-age, tibias showed higher mineral-to-matrix ratio in trabeculae (17%) and cortices (31%). and in vertebral cortices (28%). Collagen maturity was 42% higher at 10-days-of-age in Col1a2+/G610C vertebral trabeculae and in 2-month tibial cortices (12%), vertebral trabeculae (42%) and vertebral cortices (12%). Higher acid-phosphate substitution was noted in 10-day-old trabecular bone in vertebrae (31%) and in 2-month old trabecular bone in both tibia (31%) and vertebrae (4%). There was also a 16% lower carbonate-to-phosphate ratio in vertebral trabeculae and a correspondingly higher (22%) carbonate-to-phosphate ratio in 2 month-old vertebral cortices. At age 3- months-of-age, male femurs with both a Col1a2+/G610C allele and a Lrp5 high bone mass allele (Lrp5+/A214V) showed an improvement in bone composition, presenting higher trabecular carbonate-to-phosphate ratio (18%) and lower trabecular and cortical acid-phosphate substitutions (8% and 18%, respectively). Together, these results indicate that mutant collagen α2(I) chain affects both bone quantity and composition, and the usefulness of this model for studies of potential OI therapies such as anti-sclerostin treatments.

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Section: Discussionmentioning

confidence: 99%

“…These mice have been used to test the effects of enhancing Wnt signaling 6 and those of exercise 7 on bone properties. Enhancing WNT signaling in these mice has been accomplished both by crossing with the Lrp5 “high bone mass” allele ( Col1a2 + /G610C; Lrp5 + /A214V ) or by treating with an antibody to sclerostin.…”

Section: Introductionmentioning

confidence: 99%

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

Masci

Wang

Imbert

et al. 2016

Bone

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“…1) of the cortical bone in our Het mice were all within the normal range of variation for Wt mice. Curiously, significantly different observations for mice of the same age and genetic background were reported in [10]. In particular, our measurements of cortical thickness (C.Th) and torsional moment of inertia (Izz) in Wt mice on RP diet yielded C.Th=0.22±0.02 mm and Izz=0.55±0.16 mm 4 (N=5) compared to C.Th=0.39±0.02 and Izz=0.87±0.12 (N=9) in [10].…”

Section: Discussionmentioning

confidence: 97%

“…Curiously, significantly different observations for mice of the same age and genetic background were reported in [10]. In particular, our measurements of cortical thickness (C.Th) and torsional moment of inertia (Izz) in Wt mice on RP diet yielded C.Th=0.22±0.02 mm and Izz=0.55±0.16 mm 4 (N=5) compared to C.Th=0.39±0.02 and Izz=0.87±0.12 (N=9) in [10]. C.Th and Izz in our Wt and Het mice were within 1 SD of each other while ~2 SD difference between Wt and Het mice was observed in [10].…”

Section: Discussionmentioning

confidence: 97%

“…This mouse model has a Gly610 to Cys substitution in the triple helical region of the α2(I) chain of type I collagen, resulting in moderate OI [6]. It is commercially available (Jackson Laboratories, Stock No: 007248) and has been utilized in several OI studies [6-10]. G610C mice mimic the mutation and OI phenotype found in a large group of related patients from an Old Order Amish community in Lancaster County, PA. As expected for most Gly substitutions [11], the G610C mutation disrupts folding of the procollagen precursor of type I collagen and causes accumulation of misfolded procollagen in the Endoplasmic Reticulum (ER), resulting in cell stress and osteoblast malfunction [7].…”

Section: Introductionmentioning

confidence: 99%

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Makings of a brittle bone: Unexpected lessons from a low protein diet study of a mouse OI model

et al. 2016

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Glycine substitutions in type I collagen appear to cause osteogenesis imperfecta (OI) by disrupting folding of the triple helix, the structure of which requires Gly in every third position. It is less clear, however, whether the resulting bone malformations and fragility are caused by effects of intracellular accumulation of misfolded collagen on differentiation and function of osteoblasts, effects of secreted misfolded collagen on the function of bone matrix, or both. Here we describe a study originally conceived for testing how reducing intracellular accumulation of misfolded collagen would affect mice with a Gly610 to Cys substitution in the triple helical region of the α2(I) chain. To stimulate degradation of misfolded collagen by autophagy, we utilized a low protein diet. The diet had beneficial effects on osteoblast differentiation and bone matrix mineralization, but it also affected bone modeling and suppressed overall animal growth. Our more important observations, however, were not related to the diet. They revealed how altered osteoblast function and deficient bone formation by each cell caused by the G610C mutation combined with increased osteoblastogenesis might make the bone more brittle, all of which are common OI features. In G610C mice, increased bone formation surface compensated for reduced mineral apposition rate, resulting in normal cortical area and thickness at the cost of altering cortical modeling process, retaining woven bone, and reducing the ability of bone to absorb energy through plastic deformation. Reduced collagen and increased mineral density in extracellular matrix of lamellar bone compounded the problem, further reducing bone toughness. The latter observations might have particularly important implications for understanding OI pathophysiology and designing more effective therapeutic interventions.

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Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta

Paschalis

Gamsjaeger

Fratzl‐Zelman

et al. 2016

Journal of Bone and Mineral Research

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Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility that arises from decreased bone mass and abnormalities in bone material quality. OI type I represents the milder form of the disease and according to the original Sillence classification is characterized by minimal skeletal deformities and near-normal stature. Raman microspectroscopy is a vibrational spectroscopic technique that allows the determination of bone material properties in bone biopsy blocks with a spatial resolution of $1 mm, as a function of tissue age. In the present study, we used Raman microspectroscopy to evaluate bone material quality in transiliac bone biopsies from children with a mild form of OI, either attributable to collagen haploinsufficiency OI type I (OI-Quant; n ¼ 11) or aberrant collagen structure (OI-Qual; n ¼ 5), as a function of tissue age, and compared it against the previously published values established in a cohort of biopsies from healthy children (n ¼ 54, ages 1 to 23 years). The results indicated significant differences in bone material compositional characteristics between OI-Quant patients and healthy controls, whereas fewer were evident in the OI-Qual patients. Differences in both subgroups of OI compared with healthy children were evident for nanoporosity, mineral maturity/crystallinity as determined by maxima of the v 1 PO 4 Raman band, and pyridinoline (albeit in different direction) content. These alterations in bone material compositional properties most likely contribute to the bone fragility characterizing this disease.

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Hindlimb Skeletal Muscle Function and Skeletal Quality and Strength in +/G610CMice With and Without Weight-Bearing Exercise

Cited by 22 publications

References 46 publications

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

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

Makings of a brittle bone: Unexpected lessons from a low protein diet study of a mouse OI model

Evidence for a Role for Nanoporosity and Pyridinoline Content in Human Mild Osteogenesis Imperfecta

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