## <center>BMP-2, too much of a good thing?</center><br>

<div class = "text-justify">Like everybody else, scientists and clinicians hold opinions, and in some cases, they are not seeking the objective truth but a reaffirmation of their own beliefs. This could be a byproduct of testing hypotheses, sometimes it’s hard to let go when something does not work out the way we want, or other times studies get some cosmetic adjustments, so there are plenty of pigs with lipstick in science. One case that comes to my mind is the story of the bone morphogenetic protein 2 or BMP-2. This molecule attract much attention especially in the orthopedic field because so far it’s the only osteoinductive growth factor approved by the FDA that can be used in bone grafts (James et al. 2016). I am not debating on the merits of this decision since it is true that BMP-2 has osteoinductive properties, there are many studies that confirm it (Urist 1965). However, it’s interesting to see how many of these studies were biased and failed to report, or at least did not pay much attention, to the side effects of BMP-2.



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<center>https://cdn.pixabay.com/photo/2017/04/23/05/43/knee-2253047_960_720.jpg
<sub>Image CCO Creative Commons <p><a href="https://pixabay.com/en/knee-x-ray-medical-anatomy-2253047/">[Source]</a></p></sub></center> <br>
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# <center>But let’s go in order and see how and when BMP-2 is used.</center><br>

<div class = "text-justify">Despite the incredible regenerative capacity of our bone tissue, like everything else it has some limits. There are instances in which because of fractures, blast injuries, infections or resection of bone tumors we have very large bone defects that cannot heal spontaneously and require bone grafting surgeries. This number is increasing but right now we stand at about 2 million procedures every year (Keating, Simpson, and Robinson 2005), so it’s not a small problem. Ideally surgeons could use autologous bone from the patient as a scaffold to support the regeneration of the defect. This approach does not require donors and there is no risk of rejection, however, only limited amount of bone tissue can be used and there is the issue of having to damage a healthy bone. This is the reason why so much effort is dedicated towards finding alternatives. We became pretty good at using hydroxyapatite and other calcium phosphate minerals as a scaffold since they mimic the inorganic component of bone itself (Spadaro, Becker, and Bachman 1970). These mineral scaffolds are conducive of bone growth, this means that if we implant such scaffold, osteoblasts could eventually migrate into it and deposit bone extracellular matrix. But, these materials are not “osteoinducive” which means that they don’t attract and induce differentiation of stem cells towards osteoblastic phenotype. BMP-2 is an osteoinducive molecule that delivered with calcium phosphate scaffolds can work its magic, at least in an ideal world where side-effects do not exist.  But they do induce bone growth.


<center>https://upload.wikimedia.org/wikipedia/commons/7/7a/Healing_supracondylar_fracture.jpg
<sub>Image CCO Creative Commons <p><a href="(https://commons.wikimedia.org/w/index.php?search=bone+healing&title=Special%3ASearch&profile=default&fulltext=1#/media/File:Healing_supracondylar_fracture.jpg">[Source]</a></p></sub></center>
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# <center>What are the side effects of BMP-2?</center><br>

<div class = "text-justify"> First of all, studies have found that obtain an osteoinducive effect we need to deliver supraphysiological doses, this means that we need to use huge amounts that are not normally present in our body, what can possibly go wrong? Well it turns out that the presence of high concentrations of BMP-2 causes the release of cytokines such as IL-6, IL-8 and TNF-alpha and the formation of seromas  (Robin et al. 2010; Shahlaie and Kim 2008). As a consequence, there is an inflammatory response localized at the site where BMP-2 is injected (Zara et al. 2011). Our body does not react to biologics in a on/off fashion, often biologics evoke opposite responses. This a can be seen as a safety feature, so each response can be modulated if a biologic is released in disproportionate concentrations. That is also the case for BMP-2, so while it can enhance the osteogenic differentiation of stem cells it also increases the activity of cells that destroy bone, like the osteoclasts.  BMP-2 does so by inducing osteoclastogenesis in vivo (Itoh et al. 2001) which results with more osteoclasts that actively destroy and remodel bone (James et al. 2016). Since BMP-2 also induces inflammation, we need to consider that in inflammatory environments osteoclasts show also increased activity, so we have more osteoclasts that also become much more active (Hori et al. 2006).

<center>https://upload.wikimedia.org/wikipedia/commons/1/1a/Osteoclast.jpg
<sub>Image CCO Creative Commons <p><a href="(https://commons.wikimedia.org/w/index.php?search=osteoclast&title=Special%3ASearch&profile=default&fulltext=1#/media/File:Osteoclast.jpg">[Source]</a></p></sub></center>
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<div class = "text-justify"> So while it is true that more bone is being produced as a result of BMP-2, this bone was found to be of poor quality and containing low mineral density (Aghaloo et al. 2007; James et al. 2012).
Especially when used in spinal fusion surgeries, BMP-2 can have several side-effects, the worst one is probably ectopic bone formation that is caused by the leakage of BMP-2 outside the implant (James et al. 2016) . BMP-2 not only direct the differentiation of stem cells, but it can also change the phenotype of cells like  myoblasts (Chen et al. 1998), adipocytes (Fraser et al. 2006) and fibroblasts (Ishihara, Weisbrode, and Bertone 2015) that inhabit the surrounding tissues, causing some problems. You don’t have to trust me on that, few years after the approval of BMP-2, the FDA issued a warning, urging clinicians to be careful with the use of BMP-2 because it was found that from 20 to 70% of the surgeries that used BMP-2 showed some sort of BMP-2-associated complications (Carragee, Hurwitz, and Weiner 2011). This data is often overlooked in scientific publications.
With this article I don’t want to dispute the therapeutic benefits of BMP-2, probably to date we don’t have better alternatives, but I just wanted to highlight how sometimes we are biased in reporting facts.<br>


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<center><h1>References</h1></center><br>
<div class = "text-justify">Aghaloo, Tara et al. 2007. “A Study of the Role of Nell-1 Gene Modified Goat Bone Marrow Stromal Cells in Promoting New Bone Formation.” Molecular therapy : the journal of the American Society of Gene Therapy 15(10): 1872–80. http://www.ncbi.nlm.nih.gov/pubmed/17653100.<br><br>

Carragee, Eugene J, Eric L Hurwitz, and Bradley K Weiner. 2011. “A Critical Review of Recombinant Human Bone Morphogenetic Protein-2 Trials in Spinal Surgery: Emerging Safety Concerns and Lessons Learned.” The spine journal : official journal of the North American Spine Society 11(6): 471–91. http://www.ncbi.nlm.nih.gov/pubmed/21729796.<br><br>

Chen, D et al. 1998. “Differential Roles for Bone Morphogenetic Protein (BMP) Receptor Type IB and IA in Differentiation and Specification of Mesenchymal Precursor Cells to Osteoblast and Adipocyte Lineages.” The Journal of cell biology 142(1): 295–305. http://www.ncbi.nlm.nih.gov/pubmed/9660882.<br><br>
Fraser, John K, Isabella Wulur, Zeni Alfonso, and Marc H Hedrick. 2006. “Fat Tissue: An Underappreciated Source of Stem Cells for Biotechnology.” Trends in biotechnology 24(4): 150–54. http://www.ncbi.nlm.nih.gov/pubmed/16488036.<br><br>
Hori, Masateru et al. 2006. “Bone Morphogenetic Protein-2 Counterregulates Interleukin-18 MRNA and Protein in MC3T3-E1 Mouse Osteoblastic Cells.” Connective tissue research 47(3): 124–32. http://www.ncbi.nlm.nih.gov/pubmed/16753805.<br><br>
Ishihara, Akikazu, Steve E Weisbrode, and Alicia L Bertone. 2015. “Autologous Implantation of BMP2-Expressing Dermal Fibroblasts to Improve Bone Mineral Density and Architecture in Rabbit Long Bones.” Journal of orthopaedic research : official publication of the Orthopaedic Research Society 33(10): 1455–65. http://www.ncbi.nlm.nih.gov/pubmed/25418909.<br><br>
Itoh, K et al. 2001. “Bone Morphogenetic Protein 2 Stimulates Osteoclast Differentiation and Survival Supported by Receptor Activator of Nuclear Factor-KappaB Ligand.” Endocrinology 142(8): 3656–62. http://www.ncbi.nlm.nih.gov/pubmed/11459815.<br><br>
James, Aaron W. et al. 2016. “A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2.” Tissue Engineering Part B: Reviews 22(4): 284–97. http://online.liebertpub.com/doi/10.1089/ten.teb.2015.0357.<br><br>
James, Aaron W et al. 2012. “Perivascular Stem Cells: A Prospectively Purified Mesenchymal Stem Cell Population for Bone Tissue Engineering.” Stem cells translational medicine 1(6): 510–19. http://www.ncbi.nlm.nih.gov/pubmed/23197855.<br><br>
Keating, J F, A H R W Simpson, and C M Robinson. 2005. “The Management of Fractures with Bone Loss.” The Journal of bone and joint surgery. British volume 87(2): 142–50. http://www.ncbi.nlm.nih.gov/pubmed/15736731.<br><br>
Robin, Brett N et al. 2010. “Cytokine-Mediated Inflammatory Reaction Following Posterior Cervical Decompression and Fusion Associated with Recombinant Human Bone Morphogenetic Protein-2: A Case Study.” Spine 35(23): E1350-4. http://www.ncbi.nlm.nih.gov/pubmed/20938385.<br><br>
Shahlaie, Kiarash, and Kee D Kim. 2008. “Occipitocervical Fusion Using Recombinant Human Bone Morphogenetic Protein-2: Adverse Effects Due to Tissue Swelling and Seroma.” Spine 33(21): 2361–66. http://www.ncbi.nlm.nih.gov/pubmed/18827703.<br><br>
Spadaro, Joseph A., Robert O. Becker, and Charles H. Bachman. 1970. “The Distribution of Trace Metal Ions in Bone and Tendon.” Calcified Tissue Research 6(1): 49–54. http://link.springer.com/10.1007/BF02196183.<br><br>
Urist, M R. 1965. “Bone: Formation by Autoinduction.” Science (New York, N.Y.) 150(3698): 893–99. http://www.ncbi.nlm.nih.gov/pubmed/5319761.<br><br>
Zara, Janette N et al. 2011. “High Doses of Bone Morphogenetic Protein 2 Induce Structurally Abnormal Bone and Inflammation in Vivo.” Tissue engineering. Part A 17(9–10): 1389–99. http://www.ncbi.nlm.nih.gov/pubmed/21247344.


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