IL-1Ra gene transfer potentiates BMP2-mediated bone healing by redirecting osteogenesis toward endochondral ossification

Panos, Joseph A.; Coenen, Michael J.; McGlinch, Erin; Atasoy-Zeybek, Aysegul; Padilla, Consuelo Lopez de; Coghlan, Ryan; Johnstone, Brian; Ferreira, Elisabeth; Porter, Ryan M.; Vega, Rodolfo E. De la; Evans, Christopher H.

doi:10.1016/j.ymthe.2022.10.007

Cited by 10 publications

(4 citation statements)

References 43 publications

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“…Preceding this time, progressive increases in Tb.Sp and decreases in Tb.Th were observed with rhBMP2 treatment, bearing striking resemblance to the trabecular changes that occur in osteoporosis. Osteoclasts are detectable as early as Day 10 with rhBMP2 treatment and remained increased above nonhealing conditions at Week 2 until Week 4, 21 which is concordant with the peak expression of remodeling genes Dkk‐1 and Sost. The knowledge that rhBMP2 stimulates the differentiation and survival of osteoclasts 32 has led various groups to test whether anti‐catabolic agents can improve bone formation with rhBMP2.…”

Section: Discussionsupporting

confidence: 60%

Segmental defect healing in the presence or absence of recombinant human BMP2: Novel insights from a rat model

Panos

Coenen

McGlinch

et al. 2023

Journal Orthopaedic Research

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This study defined and compared the course of native, impaired and growth factor‐stimulated bone regeneration in a rat femoral defect model. A mid‐diaphyseal defect with rigid internal fixation was surgically created in the right femur of male Fischer rats and serially analyzed over 36 weeks. Native bone regeneration was modeled using a sub‐critical, 1 mm size defect, which healed uneventfully. Critical size defects of 5 mm were used to analyze impaired bone regeneration. In a third group, the 5 mm defects were filled with 11 µg of recombinant human bone morphogenetic protein 2 (rhBMP2) impregnated onto an absorbable collagen sponge, modeling its clinical use. Native bone regeneration was characterized by endochondral ossification with progressive remodeling to ultimately resemble intact femora. An endochondral response was also observed under conditions of impaired bone regeneration, but by week 8 medullary capping occurred with fibrofatty consolidation of the tissue within the defect, resembling an atrophic non‐union. rhBMP2 treatment was associated with prolonged inflammatory cytokine expression and rapid intramembranous bone formation occurring with reduced expression of cartilage‐associated collagens. Between weeks 4 and 36, rhBMP2‐treated bones demonstrated decreased trabecular number and increased trabecular separation, which resulted in inferior mechanical properties compared with bones that healed naturally. Clinical Significance: Recombinant human bone morphogenetic protein 2 (rhBMP2) is used clinically to promote healing of long bones. Our data suggest that it drives intramembraneous ossification producing an inferior regenerate that deteriorates with time. Clinical outcomes would be improved by technologies favoring endochondral regenerative ossification.

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Section: Discussionsupporting

confidence: 60%

Segmental defect healing in the presence or absence of recombinant human BMP2: Novel insights from a rat model

Panos

Coenen

McGlinch

et al. 2023

Journal Orthopaedic Research

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“…rhBMP-2 is FDA approved for spine fusion and has been increasingly used as an alternative to autografts, however both autografts and BMPs have associated complications. rhBMP-2 has reported adverse side effects that can occur including infection, inflammation, ectopic bone formation, bone resorption, neurological effects, radiculitis, and negative impacts to several other organ systems in the body 15,34–37 . In addition to these effects, BMP-induced bone formation at supra-physiological doses can produce thin and wispy bone that has cyst-like properties filled with adipose tissue and low mechanical strength 38,39 .…”

Section: Discussionmentioning

confidence: 99%

Local FK506 delivery induces osteogenesis inin vivorat bone defect and rabbit spine fusion models

Harrer,

Fulton,

Sangadala

et al. 2024

Preprint

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Bone grafting procedures are commonly used for the repair, regeneration, and fusion of bones in in a wide range of orthopaedic surgeries, including large bone defects and spine fusion procedures. Autografts are the clinical gold standard, though recombinant human bone morphogenetic proteins (rhBMPs) are often used, particularly in difficult clinical situations. However, treatment with rhBMPs can have off-target effects and significantly increase surgical costs, adding to patients′ already high economic and mental burden. Recent studies have identified that FDA-approved immunosuppressant drug, FK506 (Tacrolimus), can also activate the BMP pathway by binding to its inhibitors. This study tested the hypothesis that FK506, as a standalone treatment, could induce osteogenic differentiation of human mesenchymal stromal cells (hMSCs), as well as functional bone formation in a rat segmental bone defect model and rabbit spinal fusion model. FK506 potentiated the effect of low dose BMP-2 to enhance osteogenic differentiation and mineralization of hMSCsin vitro. Standalone treatment with FK506 delivered on a collagen sponge, produced consistent bone bridging of a rat critically-sized femoral defect with functional mechanical properties comparable to naïve bone. In a rabbit single level posterolateral spine fusion model, treatment with FK506 delivered on a collagen sponge successfully fused the L5-L6 vertebrae at rates comparable to rhBMP-2 treatment. These data demonstrate the ability of FK506 to induce bone formation in human cells and two challengingin vivomodels, and indicate FK506 can be utilized either as a standalone treatment or in conjunction with rhBMP to treat a variety of spine disorders.

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“…Researchers at the Mayo Clinic are working on applications for fracture treatment. In a study using rats, researchers confirmed that administering mRNA encoding bone morphogenetic protein 2 (BMP-2), which promotes bone formation, to the fracture site promoted bone regeneration [ 46 ].…”

Section: Mrna-based Protein Supplementation For Regenerative Medicinementioning

confidence: 99%

Cell Reprogramming and Differentiation Utilizing Messenger RNA for Regenerative Medicine

Inagaki

2023

JDB

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The COVID-19 pandemic generated interest in the medicinal applications of messenger RNA (mRNA). It is expected that mRNA will be applied, not only to vaccines, but also to regenerative medicine. The purity of mRNA is important for its medicinal applications. However, the current mRNA synthesis techniques exhibit problems, including the contamination of undesired 5′-uncapped mRNA and double-stranded RNA. Recently, our group developed a completely capped mRNA synthesis technology that contributes to the progress of mRNA research. The introduction of chemically modified nucleosides, such as N1-methylpseudouridine and 5-methylcytidine, has been reported by Karikó and Weissman, opening a path for the practical application of mRNA for vaccines and regenerative medicine. Yamanaka reported the production of induced pluripotent stem cells (iPSCs) by introducing four types of genes using a retrovirus vector. iPSCs are widely used for research on regenerative medicine and the preparation of disease models to screen new drug candidates. Among the Yamanaka factors, Klf4 and c-Myc are oncogenes, and there is a risk of tumor development if these are integrated into genomic DNA. Therefore, regenerative medicine using mRNA, which poses no risk of genome insertion, has attracted attention. In this review, the author summarizes techniques for synthesizing mRNA and its application in regenerative medicine.

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IL-1Ra gene transfer potentiates BMP2-mediated bone healing by redirecting osteogenesis toward endochondral ossification

Cited by 10 publications

References 43 publications

Segmental defect healing in the presence or absence of recombinant human BMP2: Novel insights from a rat model

Segmental defect healing in the presence or absence of recombinant human BMP2: Novel insights from a rat model

Local FK506 delivery induces osteogenesis inin vivorat bone defect and rabbit spine fusion models

Cell Reprogramming and Differentiation Utilizing Messenger RNA for Regenerative Medicine

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