Intrafibrillar mineralization deficiency and osteogenesis imperfecta mouse bone fragility

Maghsoudi-Ganjeh, Mohammad; Samuel, Jitin; Ahsan, Abu Saleh; Wang, Xiaodu; Zeng, Xiaowei

doi:10.1016/j.jmbbm.2021.104377

Cited by 19 publications

(13 citation statements)

References 74 publications

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“…When interpreted with the stiffness pattern in mineralized WT and OI collagen fibrils shown in the previous studies 32 , 33 , 40 – 42 , these PFM results in demineralized WT and OI collagens suggest physiological implications about the role of collagen piezoelectricity in intrafibrillar mineralization. In one of the previous studies 33 , dual-frequency AFM had been applied to characterize the mechanical stiffness of mineralized collagen fibrils from WT and OI mouse models.…”

Section: Resultssupporting

confidence: 71%

“…OI bone has a genetic mutation in Type I collagen, which causes structural changes and abnormal properties such as a decrease of ultimate strength and fracture toughness as well as a higher Young's modulus at the whole bone level [37][38][39] . Many studies utilizing AFM (Atomic Force Microscopy), TEM (Transmission electron microscopy), and SAXS (Small-angle X-ray scattering) confirmed that OI bone undergoes abnormal mineralization, and the OI collagen loses its heterogeneity of mechanical stiffness along the fibrils from the fibrillar level 32,33,[40][41][42] . If our hypothesis is correct, the irregular intrafibrillar mineralization of OI collagen showing uniform stiffness distribution might be attributed to its defective piezoelectricity due to the mutation of collagen molecules.…”

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confidence: 99%

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Collagen piezoelectricity in osteogenesis imperfecta and its role in intrafibrillar mineralization

Kwon

Cho

2022

Commun Biol

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Intrafibrillar mineralization plays a critical role in attaining desired mechanical properties of bone. It is well known that amorphous calcium phosphate (ACP) infiltrates into the collagen through the gap regions, but its underlying driving force is not understood. Based on the authors’ previous observations that a collagen fibril has higher piezoelectricity at gap regions, it was hypothesized that the piezoelectric heterogeneity of collagen helps ACP infiltration through the gap. To further examine this hypothesis, the collagen piezoelectricity of osteogenesis imperfecta (OI), known as brittle bone disease, is characterized by employing Piezoresponse Force Microscopy (PFM). The OI collagen reveals similar piezoelectricity between gap and overlap regions, implying that losing piezoelectric heterogeneity in OI collagen results in abnormal intrafibrillar mineralization and, accordingly, losing the benefit of mechanical heterogeneity from the fibrillar level. This finding suggests a perspective to explain the ACP infiltration, highlighting the physiological role of collagen piezoelectricity in intrafibrillar mineralization.

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Section: Resultssupporting

confidence: 71%

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confidence: 99%

Collagen piezoelectricity in osteogenesis imperfecta and its role in intrafibrillar mineralization

Kwon

Cho

2022

Commun Biol

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“…For smaller length scales, an increased compressive modulus was found in the extracellular matrix of OI bone compared to WT using FIB-machined micropillar samples, and the magnitude of increase appeared to correlate with the degree of bone mineralization and disease severity (Figure 5c) [46]. In another recent study, by subjecting OIM bone to ex-situ micropillar compression tests and through finite element modeling, Maghsoudi-Ganjeh et al proposed the possible mechanical behavior of OI bone at the fibrillar level [153]. Under compressive stress, OIM bone was found to fail in a manner consistent with brittle materials: the machined bone micropillars cracked and underwent splitting in the longitudinal direction, whereas the WT control after mechanical failure displayed a shear failure plane with localized plastic deformation zones [153].…”

Section: Osteogenesis Imperfectamentioning

confidence: 93%

“…Numerous studies have reported modified whole-bone-level mechanics of OI bone, including decreased compressive elastic modulus, reduced bending strength, increased compressive strength, increased hardness, and, most notably, heightened brittleness compared to healthy counterparts [142,143,152,153]. For smaller length scales, an increased compressive modulus was found in the extracellular matrix of OI bone compared to WT using FIB-machined micropillar samples, and the magnitude of increase appeared to correlate with the degree of bone mineralization and disease severity (Figure 5c) [46].…”

Section: Osteogenesis Imperfectamentioning

confidence: 99%

“…In another recent study, by subjecting OIM bone to ex-situ micropillar compression tests and through finite element modeling, Maghsoudi-Ganjeh et al proposed the possible mechanical behavior of OI bone at the fibrillar level [153]. Under compressive stress, OIM bone was found to fail in a manner consistent with brittle materials: the machined bone micropillars cracked and underwent splitting in the longitudinal direction, whereas the WT control after mechanical failure displayed a shear failure plane with localized plastic deformation zones [153]. It was suggested that the misorientation of the mineral crystals, along with a lack of intrafibrillar mineralization, contribute to a compromised load transfer mechanism between the mineral and collagen phases of bone, leading to poor mechanical performance of the bone [153].…”

Section: Osteogenesis Imperfectamentioning

confidence: 99%

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Nanoscale Imaging and Analysis of Bone Pathologies

et al. 2021

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Understanding the properties of bone is of both fundamental and clinical relevance. The basis of bone’s quality and mechanical resilience lies in its nanoscale building blocks (i.e., mineral, collagen, non-collagenous proteins, and water) and their complex interactions across length scales. Although the structure–mechanical property relationship in healthy bone tissue is relatively well characterized, not much is known about the molecular-level origin of impaired mechanics and higher fracture risks in skeletal disorders such as osteoporosis or Paget’s disease. Alterations in the ultrastructure, chemistry, and nano-/micromechanics of bone tissue in such a diverse group of diseased states have only been briefly explored. Recent research is uncovering the effects of several non-collagenous bone matrix proteins, whose deficiencies or mutations are, to some extent, implicated in bone diseases, on bone matrix quality and mechanics. Herein, we review existing studies on ultrastructural imaging—with a focus on electron microscopy—and chemical, mechanical analysis of pathological bone tissues. The nanometric details offered by these reports, from studying knockout mice models to characterizing exact disease phenotypes, can provide key insights into various bone pathologies and facilitate the development of new treatments.

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Whole‐Body Metabolism and the Musculoskeletal Impacts of Targeting Activin A and Myostatin in Severe Osteogenesis Imperfecta

Omosule,

Joseph,

Weiler

et al. 2023

JBMR Plus

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Mutations in the COL1A1 and COL1A2 genes, which encode type I collagen, are present in around 85%-90% of osteogenesis imperfecta (OI) patients. Because type I collagen is the principal protein composition of bones, any changes in its gene sequences or synthesis can severely affect bone structure. As a result, skeletal deformity and bone frailty are defining characteristics of OI. Homozygous oim/oim mice are utilized as models of severe progressive type III OI. Bone adapts to external forces by altering its mass and architecture. Previous attempts to leverage the relationship between muscle and bone involved using a soluble activin receptor type IIB-mFc (sActRIIB-mFc) fusion protein to lower circulating concentrations of activin A and myostatin. These two proteins are part of the TGF-β superfamily that regulate muscle and bone function. While this approach resulted in increased muscle masses and enhanced bone properties, adverse effects emerged due to ligand promiscuity, limiting clinical efficacy and obscuring the precise contributions of myostatin and activin A. In this study, we investigated the musculoskeletal and whole-body metabolism effect of treating 5-weekold wildtype (Wt) and oim/oim mice for 11 weeks with either control antibody (Ctrl-Ab) or monoclonal anti-activin A antibody (ActA-Ab), anti-myostatin antibody (Mstn-Ab), or a combination of ActA-Ab and Mstn-Ab (Combo). We demonstrated that ActA-Ab treatment minimally impacts muscle mass in oim/oim mice, whereas Mstn-Ab and Combo treatments substantially increased muscle mass and overall lean mass regardless of genotype and sex. Further, while no improvements in cortical bone microarchitecture were observed with all treatments, minimal improvements in trabecular bone microarchitecture were observed with the Combo treatment in oim/oim mice. Our findings suggest that individual or combinatorial inhibition of myostatin and activin A alone is insufficient to robustly improve femoral biomechanical and microarchitectural properties in severely affected OI mice.

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Intrafibrillar mineralization deficiency and osteogenesis imperfecta mouse bone fragility

Cited by 19 publications

References 74 publications

Collagen piezoelectricity in osteogenesis imperfecta and its role in intrafibrillar mineralization

Collagen piezoelectricity in osteogenesis imperfecta and its role in intrafibrillar mineralization

Nanoscale Imaging and Analysis of Bone Pathologies

Whole‐Body Metabolism and the Musculoskeletal Impacts of Targeting Activin A and Myostatin in Severe Osteogenesis Imperfecta

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