Inhibition of <scp>TGF</scp>‐β Increases Bone Volume and Strength in a Mouse Model of Osteogenesis Imperfecta

Greene, Benjamin; Russo, Ryan J.; Dwyer, Shannon; Malley, Katie; Roberts, Errin; Serrielo, Joseph; Piepenhagen, Peter; Cummings, Sheila; Ryan, Susan; Zarazinski, Christine; Uppuganti, Sasidhar; Bukanov, Nikolai; Nyman, Jeffry S.; Cox, Megan K.; Liu, Shiguang; Ibraghimov‐Beskrovnaya, Oxana; Sabbagh, Yves

doi:10.1002/jbm4.10530

Cited by 22 publications

(24 citation statements)

References 39 publications

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“…However, treatment with the 4 mg/kg dose resulted in sustained suppression of bone turnover, as shown by plasma Ocn levels. The latter effect is consistent with murine studies that show neutralizing TGF-β results in a decrease in bone turnover and an increase in bone mass ( 25 , 31 ). The effects on LS aBMD were more variable.…”

Section: Discussionsupporting

confidence: 90%

“…Genotype and clinical severity are likely to have an influence on the response to therapy. Recent preclinical studies have shown that higher and more frequent dosing of anti–TGF-β therapy has a more significant effect on “normalizing” the coupling of bone resorption and bone formation, resulting in decreased bone remodeling, increased bone mineral density, and improved biomechanical properties ( 31 ). Furthermore, whereas mild and moderately severe murine models of collagen-related OI (G610C Col1a2 tm1.1Mcbr and Crtap –/– ) have shown a response to anti–TGF-β treatment, such response has not been observed in a more severe model ( Col1a1 Jrt/+ ) that has features of Ehlers-Danlos syndrome and OI ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

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Targeting TGF-β for treatment of osteogenesis imperfecta

Song¹,

Nagamani²,

Nguyen³

et al. 2022

Journal of Clinical Investigation

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BACKGROUND Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI. METHODS Histology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed. RESULTS OI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD. CONCLUSION Increased TGF-β signaling is a driver pathogenic mechanism in OI. Anti–TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover. TRIAL REGISTRATION ClinicalTrials.gov NCT03064074. FUNDING Brittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Targeting TGF-β for treatment of osteogenesis imperfecta

Song¹,

Nagamani²,

Nguyen³

et al. 2022

Journal of Clinical Investigation

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“…Also TGF-β binds to bone resorption and formation and recruits bone progenitor cells to the site of bone resorption. 39 TGF-β gene is located in the long arm of chromosome 19, and the gene is described as 5 SNPs, which are −800G/A (rs1800468) and −509C/T (rs1800469) promoter region and +896T/C (rs1982073), +915G/C (rs1800471), +29T/C (re1800470) coding region, respectively. Multiple studies have confirmed that TGF-β polymorphism is associated with disease susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Association of IL-6 and TGF-β Gene Polymorphisms with the Risk of Thoracolumbar Osteoporotic Vertebral Compression Fractures

Xiong

Yang

Yan³

et al. 2022

PGPM

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Purpose Osteoporotic vertebral compression fracture (OVCF) is a common disease in the elderly, and genetic factors play a key role in its occurrence. The present study was conducted to investigate the association between interleukin-6 ( IL-6 ) and the transforming growth factor ( TGF-β ) gene polymorphisms and the occurrence of thoracolumbar OVCF. Patients and Methods This case–control study recruited 146 patients with OVCF and 144 osteoporosis patients as the control group. Genotypes of the IL-6 rs1800796 and TGF-β rs1982073 were analyzed by sequencing. Genotype distribution and allelic frequencies were investigated by the χ 2 test. Odds ratios (OR) and 95% confidence intervals (CI) evaluated the relationship of IL-6 or TGF-β polymorphism and OVCF susceptibility. Results Allele G and genotype GG of IL-6 rs1800796 was more frequent in patients with OVCF (40.07% vs.28.47%; 19.18% vs.7.64%) compared with controls. GG genotype (OR=3.394, 95% CI=1.560–7.385, P < 0.001) and G allele (OR=1.680, 95% CI=1.187–2.376, P < 0.001) of IL-6 rs1800796 was significantly associated with increased risk of OVCF. What is more, CT and TT genotypes (41.78 vs.51.39; 19.86 vs.26.39) and allele T (40.75 vs 52.08) of TGF-β rs1982073 were less frequent in OVCFs, more common in controls and protective against OVCF risk (OR=0.436, 95% CI=0.228–0.835, P = 0.012; OR=0.615, 95% CI=0.443–0.855, P = 0.004). Conclusion Our results suggest that the G allele and GG genotype of IL-6 rs1800796 may contribute to increased susceptibility to OVCF in elderly Chinese. In contrast, CT and TT genotypes and the T allele of TGF-β rs1982073 may contribute to lower susceptibility of OVCF.

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“…Alkaline phosphatase (ALP) staining (C3206, Beyotime, Haimen, China) and staining of mineralized nodules with alizarin red (G1452, Solarbio, Beijing, China) were performed following the manufacturers' instructions. The proximal tibiae were analyzed using a 1500×1800‐μm region of interest (ROI) 150 μm from the growth plate in a grid‐like pattern along the ROI 34 . Five fields of each slide and five slides were randomly selected for analysis 35 …”

Section: Methodsmentioning

confidence: 99%

Bindarit Reduces Bone Loss in Ovariectomized Mice by Inhibiting CCL2 and CCL7 Expression via the NF‐κB Signaling Pathway

Yuan

Wang

et al. 2022

Orthopaedic Surgery

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Objective To investigate the changes in proinflammatory cytokines and chemokines, namely, C‐C motif ligand (CCL) 2 and CCL7, in postmenopausal osteoporosis (PMOP) and to develop a new drug, bindarit (Bnd), for PMOP in an ovariectomized (OVX) mouse model. Methods Bone marrow macrophages (BMMs) from the femurs of five women with PMOP and five premenopausal women without osteoporosis were detected by RNA sequencing. BMMs from mice were differentiated into osteoclasts and treated with a synthetic inhibitor of CCL2 and CCL7, Bnd, or 17 beta estradiol (E2). Mouse BMMs were differentiated into osteoclasts with or without Bnd for 7 days and analyzed by RNA sequencing. Osteoblasts of mice were induced to undergo osteoblastogenesis and treated with Bnd. OVX mice were treated with E2 or Bnd after surgery. The protein and mRNA expression of CCL2 and CCL7 was detected using immunostaining and qPCR, respectively, in OVX and aged mice and in cells cultured in vitro. Osteoclast formation was detected using a tartrate‐resistant acid phosphatase (TRAP) assay in vitro and in vivo. Alkaline phosphatase (ALP), runt‐related transcription factor 2 (Runx2) and osteocalcin (OCN) were detected using immunostaining to evaluate osteogenesis. Microcomputed tomography was conducted to analyze trabecular bone parameters, the structure model index, bone mineral density and other variables. Nuclear factor‐κB (NF‐κB) signaling pathway‐related protein phosphorylation of IKKα/β (p‐IKKα/β) and p‐NFκB p65 was examined using western blotting. Results CCL2, CCL7 and their receptor of C‐C chemokine receptor‐2 (CCR2), and the NF‐κB signaling pathway, were significantly increased in women with PMOP. CCL2 and CCL7 protein and mRNA expression was increased in OVX mice and aged female mice, but the increases were attenuated by E2 and Bnd. E2 and Bnd effectively inhibited osteoclastogenesis and the protein expression of CCL2 and CCL7 both in vitro and in vivo and reduced bone loss in OVX mice. Bnd did not affect the mineralization of osteoblasts directly in vitro but reduced bone turnover in vivo. p‐IKKα/β and p‐NFκB p65 levels were increased in BMMs of mice after differentiation into osteoclasts but were significantly decreased by Bnd. Conclusion The proinflammatory cytokines and chemokines CCL2, CCL7 and CCR2 were correlated with PMOP. Bnd attenuated the increases in CCL2 and CCL7 levels to affect osteoporosis in OVX mice via the NFκB signaling pathway. Thus, Bnd may be useful as a new therapeutic for the prevention of PMOP.

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Inhibition of TGF‐β Increases Bone Volume and Strength in a Mouse Model of Osteogenesis Imperfecta

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 22 publications

References 39 publications

Targeting TGF-β for treatment of osteogenesis imperfecta

Targeting TGF-β for treatment of osteogenesis imperfecta

Association of IL-6 and TGF-β Gene Polymorphisms with the Risk of Thoracolumbar Osteoporotic Vertebral Compression Fractures

Bindarit Reduces Bone Loss in Ovariectomized Mice by Inhibiting CCL2 and CCL7 Expression via the NF‐κB Signaling Pathway

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