Specific Characteristic of Hyperplastic Callus in a Larger Cohort of Osteogenesis Imperfecta Type V

Zheng, Wenbin; Hu, Jing; Jia, Zhang; Yang, Zheng; Wang, Ou; Jiang, Yan; Xia, Weibo; Xing, Xiaoping; Yu, Wei; Li, Mei

doi:10.1007/s00223-021-00932-2

Cited by 2 publications

(2 citation statements)

References 36 publications

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“…Only a few studies have looked at histological appearance and matrix composition at the tissue level. Histological analyses of hyperplastic callus have revealed very heterogeneous tissue, containing edematous areas with occasional atrophic muscle fibers, hypercellular woven bone, fibrochondroid and chondroid tissue [42][43][44][45][46][47], possibly alluding to perturbed events in mesenchymal stem cells differentiation. The periosteal bone expansion is not always linked to hyperplastic callus, indicating that more subtle intramembranous periosteal events may be involved [15].…”

Section: Discussionmentioning

confidence: 99%

The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts

Maranda

Gaumond

Moffatt

2022

IJMS

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BRIL (bone restricted ifitm-like; also known as IFITM5) is a transmembrane protein expressed in osteoblasts. Although its role in skeletal development and homeostasis is unknown, mutations in BRIL result in rare dominant forms of osteogenesis imperfecta. The pathogenic mechanism has been proposed to be a gain-of or neomorphic function. To understand the function of BRIL and its OI type V mutant (MALEP BRIL) and whether they could activate signaling pathways in osteoblasts, we performed a luciferase reporter assay screen based on the activity of 26 transcription factors. When overexpressed in MC3T3-E1 and MLO-A5 cells, the MALEP BRIL activated the reporters dependent on MEF2, NFATc, and NR4A significantly more. Additional co-transfection experiments with MEF2C and NFATc1 and a number of their modulators (HDAC4, calcineurin, RCAN, FK506) confirmed the additive or synergistic activation of the pathways by MALEP, and suggested a coordinated regulation involving calcineurin. Endogenous levels of Nr4a members, as well as Ptgs2, were upregulated by MALEP BRIL. Y2H and co-immunoprecipitation indicated that BRIL interacted with CAML, but its contribution as the most upstream stimulator of the Ca2+-calcineurin-MEF2/NFATc cascade was not confirmed convincingly. Altogether the data presented provide the first ever readout to monitor for BRIL activity and suggest a potential gain-of-function causative effect for MALEP BRIL in OI type V, leading to perturbed signaling events and gene expression.

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Section: Discussionmentioning

confidence: 99%

The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts

Maranda

Gaumond

Moffatt

2022

IJMS

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“…The remaining patients with OI have autosomal recessive forms due to biallelic mutations in genes that encode proteins involved in collagen processing, post-translational modification, and crosslinking of type I collagen or in genes involved in osteoblast differentiation or bone mineralization ( 2 ). The clinical spectrum of OI ranges widely from mild to lethal, including the mildest form (type I), perinatal lethality (type II), the most severe form among surviving patients (type III), an intermediate form between type I and type III (type IV), and the unique type with interosseous membrane calcification of the forearm and/or hypertrophic callus (type V) ( 3 , 4 ).…”

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confidence: 99%

Efficacy and Safety of Denosumab vs Zoledronic Acid in OI Adults: A Prospective, Open-Label, Randomized Study

Lin,

Hu,

Zhou

et al. 2024

The Journal of Clinical Endocrinology &Amp; Metabolism

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Objective To evaluate the efficacy and safety of denosumab and zoledronic acid in adult patients with OI. Design and methods This was a prospective, open-label study. Patients were randomized to receive denosumab 60 mg every 6 months or zoledronic acid 5 mg once for 12 months. Pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing. Percentage changes in the areal bone mineral density (aBMD), trabecular bone score (TBS) and bone turnover biomarkers (BTMs) from baseline to 6 and 12 months of treatment, as well as safety, were evaluated. Results A total of 51 OI adults (denosumab: 25, zoledronic acid: 26) were included, of whom 49 patients had identified pathogenic mutations. At 12 months, aBMD at the lumbar spine and total hip significantly increased by 4.34% (P = 0.005) and 1.45% (P = 0.023) in denosumab group and by 4.92% (P = 0.006) and 2.02% (P = 0.016) in zoledronic acid group, respectively. TBS showed an increasing trend by 1.39% and 2.70% in denosumab and zoledronic acid groups, respectively. Serum levels of β-CTX and ALP markedly decreased after denosumab treatment. Percentage changes in aBMD, TBS and BTMs during the treatment were similar between the two groups. OI patients with milder phenotypes showed a significantly higher increase in the TBS after 12 months of denosumab treatment than those with more severe phenotypes (P = 0.030). During the study period, denosumab group had fewer adverse events than the zoledronic acid group. Conclusion Denosumab effectively increases aBMD in OI adults, with similar efficacy to zoledronic acid. Long-term and large-sample studies are needed to confirm the anti-fracture efficacy and safety of denosumab in adult OI patients.

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Specific Characteristic of Hyperplastic Callus in a Larger Cohort of Osteogenesis Imperfecta Type V

Cited by 2 publications

References 36 publications

The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts

The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts

Efficacy and Safety of Denosumab vs Zoledronic Acid in OI Adults: A Prospective, Open-Label, Randomized Study

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