Research Uncovers Mechanism of the BMP-2 Related Complications and Previously Unknown Source of Pluripotent Stem Cells

Lead author Michael H. Heggeness, MD, and Jeffrey C. Wang, MD, comment

In research designed to uncover the mechanisms behind nerve-related complications resulting from bone morphogenic protein 2 (BMP-2) exposure, researchers uncovered a population of cells residing in peripheral nerves that, when stimulated by injury (including accidental BMP-2 exposure), proliferate and differentiate into stem cells that appear to have embryonic differentiation potential. The findings were reported in the February issue of The Spine Journal.

flasks in a laboratory

“We believe that we have likely illuminated critical features of the mechanism of how the BMP-2 molecule stimulates bone formation, specifically, by inducing stem cell proliferation,” Dr. Heggeness and colleagues noted in the study.

In addition, “We now have a new understanding of how the body heals itself, and that connects in a profound way to a variety of potential clinical implications,” said lead author Michael H. Heggeness, MD, Professor of Orthopaedic Surgery at the University of Kansas School of Medicine-Wichita.

Study Design
The study was designed to investigate how to make spine surgeries involving use of BMP-2 safer, so that potential nerve-related complications of BMP-2 could be avoided. BMP-2, which is used to promote bone formation in spine procedures, has been linked to complications, including pharyngeal swelling, new-onset sciatica, and retrograde ejaculation, the researchers noted in their paper.

The researchers found that murine peripheral nerves exposed to small quantities of diluted recombinant human BMP-2 triggered a surge of cell proliferation within the nerves that migrated into surrounding tissue. When they isolated those cells for culture and characterization using immunohistochemical stains and real-time polymerase chain reaction techniques, the cells were found to express embryonic stem cell markers KLF4, Sox2, c-Myc, and Oct4.

“Based on the Yamanaka Nobel Prize-winning studies, adult cells induced in culture to express these four genes possess the wide differentiation potential of embryonic stem cells,” which are commonly referred to as induced pluripotent stem cells, the study authors noted in the paper.

“Data suggest that this is a previously unknown and undescribed variety of pluripotent stem cells that can be obtained from adult animals without the use of retroviruses or any direct manipulation of genes,” the authors wrote. “We suggest that they be referred to as NErve Derived Adult Pluripotent Stem cells or NEDAPS cells.”

Stem Cell Proliferation is Triggered by Nerve Insult
Dr. Heggeness said that this proliferation of NEDAPS cells in peripheral nerves is not unique to BMP-2 exposure. “If you insult the nerve in many other ways, such as squeezing it tightly with surgical forceps, pulling on it, or exposing it to a lot of bleeding, the same signals are transmitted and the same pluripotent stem cells pour out of the nerve looking to fix what is broken,” Dr. Heggeness told SpineUniverse.

Potential Implications
Dr. Heggeness believes that this finding of NEDAPS cell proliferation explains why patients with diabetic neuropathy develop fractures and wounds in their lower limbs that do not heal. “The cells within the peripheral nerves that would normally participate in healing the injuries are compromised or dead,” Dr. Heggeness told SpineUniverse. The same theory would apply to the nonhealing wounds in leprosy patients, he added.

Commentary

Jeffrey C. Wang, MD
Chief, Orthopaedic Spine Service
Co-Director, USC Spine Center
Professor of Orthopaedic Surgery and Neurosurgery
USC Spine Center
Los Angeles, CA

We know that there are some potential complications associated with the use of rhBMP-2. Although it can result in possibly a more reliable spinal fusion and quicker healing of the fusion, we are learning more and more about this as we gather data and produce good basic science research. This study analyzes some of the potential mechanisms by which the use of this protein, when exposed directly to the neural elements, can result in adverse changes that can lead to problems with the nerves. I think this controlled basic science study is a nice way to analyze the process in an animal model, and allow us to gain some insight into how this can adversely affect nerves. This may be applicable to the human situation and may explain why some patients have developed some nerve issues after potential exposure to the protein.

I think this is more information that the clinician needs to take into account when potentially using rhBMP-2 in their patients. The findings may confirm what some surgeons have seen clinically, and certainly may change the way [use of rhBMP-2] is applied when there are exposed nerves. Others may use some types of sealants to protect the nerves if rhBMP-2 is used near the neural elements. I think this information may give us some answers as to why some patients have nerve issues, and may change whether rhBMP-2 is used in certain types of surgeries.

Clearly, all doctors want the best for their patients, and all surgeons want their patients to do well. There are numerous studies showing that rhBMP-2 can be used in many applications and results in rapid healing of the spinal fusion, and that the majority of patients have no complications.

However, we have all seen potential complications with the use of this protein, as we see potential complications with the use of almost any medication, drug, or any surgery. Even taking an aspirin or using acetaminophen, can result in complications in some patients. I think when rhBMP-2 is used, careful counseling of the patient describing all the potential problems should become part of the routine, prior to making a shared-decision on whether this is something the patient wants to use. If someone were to search information about this protein, one would find a lot of sensationalized information, a lot of misinformation, a lot of lawyers seeking lawsuits against the company and doctors, and it is confusing for patients. The best information is from real science and medical studies that are peer-reviewed and published in the highest evidence scientific journals.

Updated on: 03/20/17
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