Safety and Efficacy of Recombinant Human Bone Morphogenetic Protein 2 on Cranial Defect Closure in the Pediatric Population

Beidas, Omar E.; Deschamps-Braly, Jordan C.; Morgan, Aaron; Workman, Meredith; Knotts, Christopher D.; Denny, Arlen D.; Amm, Christian A. El

doi:10.1097/scs.0b013e318256657c

Cited by 16 publications

(14 citation statements)

References 42 publications

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“…4 However, extended clinical use of BMP-2/ACS has revealed increasing concerns regarding inflammation-related adverse events such as soft-tissue swelling, 5, 6 seroma, 7, 8 bone resorption, 9 and the low osteoinductive efficacy of BMP-2. 4, 10, 11, 12 These complications have resulted in unsatisfactory long-term outcomes in clinical applications. 4, 13, 14 …”

mentioning

confidence: 99%

Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation

et al. 2014

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In patients who were treated with exogenous BMP-2 to repair bone fractures or defects, the levels of the inflammatory cytokines such as TNF-α and IL-1β in sera are significantly elevated, which may affect the outcome of bone regeneration. Mitogen-activated protein kinase (MAPK) cascades such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase 1/2 (JNK1/2) have a crucial role in osteogenic differentiation and are activated by both BMP-2 and TNF-α/IL-1β. However, previous studies suggested that the effects of BMP-2 and TNF-α/IL-1β in osteoblastic differentiation are opposite. Here, we investigated the exact role of MAPKs in a BMP-2 and TNF-α/IL-1β co-existed condition. Treatment with TNF-α/IL-1β inhibited BMP-2-induced alkaline phosphatase activity, calcium deposition, osteogenic transcriptional factor Runx2, and the expression of osteogenic markers in C2C12 and MC3T3-E1 cells. This inhibitory effect was independent of the canonical BMP/Smad pathway, suggesting the presence of an alternate regulatory pathway for BMP-2-induced Runx2 activity and subsequent osteoblastic differentiation. We then confirmed that BMP-2, TNF-α, and IL-1β alone can activate p38, ERK1/2, and JNK1/2, respectively. However, only inhibition of p38 and ERK1/2 signaling were required to modulate BMP-2-induced Runx2 expression. Finally, we determined that TNF-α/IL-1β decreased BMP-2-induced Runx2 expression through the activation of p38 and ERK1/2 signaling. Furthermore, strong activation of p38 and ERK1/2 signaling by transfection with CA-MKK3 or CA-MEK1 inhibited BMP-2-induced Runx2 expression and osteoblastic differentiation in C2C12 and MC3T3-E1 cells. Based on these results, we conclude that TNF-α/IL-1β- and BMP-2-activated p38 and ERK1/2 signaling have opposing roles that converge on Runx2 to regulate osteoblastic differentiation. The elucidation of these mechanisms may hasten the development of new strategies and improve the osteoinductive efficacy of BMP-2 in the clinic to enhance osteoblastic differentiation and bone formation.

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confidence: 99%

Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation

et al. 2014

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“…Spinal surgery 27-34 rhBMP-2 may not have clinical advantage over bone grafts in spine fusion due to associated harm. Paediatric use 21,22 BMP-2 has been shown to be successful in the treatment of spinal fusion with a 100% fusion rate in paediatric patients.…”

Section: Bmp-2: Usesmentioning

confidence: 99%

“…More studies are required to determine safe doses and long-term effects for children Paediatric: cranial defect closures [22] 36 Humans A slight higher closure rate compared to control group, no report of brain oedema, herniation and airway problems More studies are required to determine safe doses and long-term effects for children promote healing, but is associated with high patient morbidity and decreased quality of life. [15] Govender et al [15] carried out a study on 420 patients which showed promising results.…”

Section: Needs Further Research In Human Trialsmentioning

confidence: 99%

“…Patients receiving the cranial defect closure augmented with BMP-2 experienced a slightly higher closure rate in comparison with the control group that underwent cranial defect closure using cranial bone shavings. [22] There were no reports of brain oedema, herniation and airway problems. [22] Although there are reports of successful use of BMP-2 in children, more studies are required to determine safe doses and long-term effects.…”

Section: Needs Further Research In Human Trialsmentioning

confidence: 99%

“…[22] There were no reports of brain oedema, herniation and airway problems. [22] Although there are reports of successful use of BMP-2 in children, more studies are required to determine safe doses and long-term effects.…”

Section: Needs Further Research In Human Trialsmentioning

confidence: 99%

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Bone morphogenetic protein-2 and bone therapy: successes and pitfalls

Poon

Kha

Tran

et al. 2016

Journal of Pharmacy and Pharmacology

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Objectives Bone morphogenetic proteins (BMPs), more specifically BMP-2, are being increasingly used in orthopaedic surgery due to advanced research into osteoinductive factors that may enhance and improve bone therapy. There are many areas in therapy that BMP-2 is being applied to, including dental treatment, open tibial fractures, cancer and spinal surgery. Within these areas of treatment, there are many reports of successes and pitfalls. This review explores the use of BMP-2 and its successes, pitfalls and future prospects in bone therapy. Methods The PubMed database was consulted to compile this review. Key findings With successes in therapy, there were descriptions of a more rapid healing time with no signs of rejection or infection attributed to BMP-2 treatment. Pitfalls included BMP-2 'off-label' use, which lead to various adverse effects. Conclusions Our search highlighted that optimising treatment with BMP-2 is a direction that many researchers are exploring, with areas of current research interest including concentration and dose of BMP-2, carrier type and delivery.

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