Sir,

We appreciate Dr. Epstein's raising awareness of potential complications related to the usage of recombinant Bone Morphogenetic Protein (BMP).[ 5 ] Certainly, the list of potential adverse events are concerning to numerous audiences, including dentists, oral surgeons, orthopedists, and the biomedical science community.[ 6 ] However, in addition to the well-documented complications such as marked dysphagia, acute upper airway inflammation, and respiratory distress, Dr Epstein raises the suspicion of a possible connection between BMP usage for spine fusion and the development of pulmonary arterial hypertension (PAH). We respectfully disagree with this point of view, and wish to highlight evidence that PAH likely develops from aberrant loss-of-function of the BMP pathway rather than over-activation of the BMP pathway, as would be expected if recombinant BMP were to diffuse away from a local delivery site.

In 2000, two independent groups provided the first connection between PAH pathogenesis and the BMP pathway by identifying heterozygous mutations in the gene encoding the BMP Receptor Type 2 (BMPR2) underlie a rare, familial form of PAH.[ 4 8 ] Since then, hundreds of distinct mutations in BMPR2 have been identified, and numerous genetic studies in mouse models have demonstrated that loss of or impairment of BMPR2-dependent signalling predisposes animals to developing pulmonary hypertension (PH), which is consistent with the fact that BMP signal transduction and pathway components are generally down-regulated in the lungs of PH patients.[ 10 ] Animal models also suggest that various strategies aimed at increasing BMP signaling in the pulmonary vasculature – such as increasing BMPR2 expression,[ 2 7 11 12 ] inhibiting a BMP antagonist that sequesters BMP ligands,[ 3 ] alleviating BMP pathway repression at the receptor-level using the Food and Drug Association (FDA)-approved drug tacrolimus,[ 13 ] or potentiating BMP pathway signal transduction using the FDA-approved phosphodiesterase-5 inhibitor sildenafil[ 14 ] – may be beneficial in treating PAH. Furthermore, systemic delivery of the BMP ligand BMP9 reverses established disease in mouse and rat models of PH[ 9 ] rather than promoting its development. While it might be argued that BMP2 and BMP9 ligands may have different, even opposing effects, because of differences in their receptor selectivity,[ 10 ] mice with heterozygous null Bmp2 mutations develop more severe PH than their wild type littermates,[ 1 ] suggesting that BMP2 also has protective effects against the development of PH.

For these reasons, we contend that the experimental evidence indicates that BMP signalling serves a protective role against the development of PAH. While we agree there are important side effects associated with the use of recombinant BMP in spine fusion, and these must be taken into consideration, it is unlikely that development of PAH is one of them.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Anderson L, Lowery JW, Frank DB, Novitskaya T, Jones M, Mortlock DP. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol. 2010. 298: R833-42

2. Brock M, Samillan VJ, Trenkmann M, Schwarzwald C, Ulrich S, Gay RE. AntagomiR directed against miR-20a restores functional BMPR2 signalling and prevents vascular remodelling in hypoxia-induced pulmonary hypertension. Eur Heart J. 2014. 35: 3203-11

3. Ciuclan L, Sheppard K, Dong L, Sutton D, Duggan N, Hussey M. Treatment with anti-gremlin 1 antibody ameliorates chronic hypoxia/SU5416-induced pulmonary arterial hypertension in mice. Am J Pathol. 2013. 183: 1461-73

4. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G. Familial primary pulmonary hypertension (gene PPH 1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000. 67: 737-44

5. Epstein NE. Commentary: Bone morphogenetic protein's contribution to pulmonary artery hypertension: Should this raise concern for patients undergoing spinal fusions with bone morphogenetic protein?. Surg Neurol Int. 2014. 5: S570-3

6. Epstein NE. Complications due to the use of BMP/INFUSE in spine surgery: The evidence continues to mount. Surg Neurol Int. 2013. 4: S343-52

7. Feng F, Harper RL, Reynolds PN. BMPR2 gene delivery reduces mutation-related PAH and counteracts TGF-beta-mediated pulmonary cell signalling. Respirology. 2016. 21: 526-32

8. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, Loyd JE. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000. 26: 81-4

9. Long L, Ormiston ML, Yang X, Southwood M, Graf S, Machado RD. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nature Med. 2015. 21: 777-85

10. Lowery JW, de Caestecker MP. BMP signaling in vascular development and disease. Cytokine Growth Factor Rev. 2010. 21: 287-98

11. Reynolds AM, Holmes MD, Danilov SM, Reynolds PN. Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur Respir J. 2012. 39: 329-43

12. Reynolds AM, Xia W, Holmes MD, Hodge SJ, Danilov S, Curiel DT. Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2007. 292: L1182-92

13. Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013. 123: 3600-13

14. Yang J, Li X, Al-Lamki RS, Wu C, Weiss A, Berk J. Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2013. 33: 34-42