BMP2-Induced Inflammation Can Be Suppressed by the Osteoinductive Growth Factor NELL-1

Abstract

Bone-morphogenetic protein 2 (BMP2) is currently the only Food and Drug Administration-approved osteoinductive growth factor used in clinical settings for bone regeneration and repair. However, the use of BMP2 is encumbered by numerous clinical complications, including postoperative inflammation and life-threatening cervical swelling. Thus, methods to prevent BMP2-induced inflammation would have far-reaching clinical implications toward improving current BMP2-based methods for bone regeneration. For the first time, we investigate the potential role of the growth factor Nel-like molecule-1 (NELL-1) in inhibiting BMP2-induced inflammation. Adult rats underwent a femoral bone onlay procedure, treated with either BMP2 protein (4 mg/mL), NELL-1 protein (4 mg/mL), or both proteins combined. Animals were evaluated at 3, 7, and 14 days postoperatively by histology, histomorphometry, immunohistochemistry, and real-time PCR for markers of inflammation (TNFa, IL6). The relative levels of TNFa and IL6 in serum were also detected by ELISA. The mechanism for NELL-1's antiinflammatory effect was further assessed through examining inflammatory markers and generation of reactive oxygen species (ROS) in the mouse embryonic fibroblast NIH3T3 cells. BMP2 significantly induced local inflammation, including an early and pronounced polymorphonuclear cell infiltration accompanied by increased expression of TNFa and IL6. Treatment with NELL-1 alone elicited no significant inflammatory response. However, NELL-1 significantly attenuated BMP2-induced inflammation by all markers and at all timepoints. These local findings were also confirmed using systemic serum inflammatory biomarkers (TNFa, IL6). In each case, NELL-1 fully reversed BMP2-induced systemic inflammation. Lastly, our findings were recapitulated in vitro, where NELL-1 suppressed BMP2 induced expression of inflammatory markers, as well as NF-kB transcriptional activity and generation of ROS. BMP2-induced inflammation is a serious public health concern with potentially life-threatening complications. In the present study, we observed that the growth factor, NELL-1, significantly attenuates or completely reverses BMP2-induced inflammation. The mechanisms of NELL-1's anti-inflammatory effect are only partially elucidated, and may include reduction of NF-kB transcriptional activity or ROS generation.

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

“…37,77 Finally, using a femoral onlay model, 12 we found that NELL-1 does not mediate inflammatory cell infiltration, in contrast to BMP2. 78 Based on these observations, we believe that NELL-1 is not directly chemotactic, but instead promotes a more directed lineage specification of BMP2-induced or recruited progenitors toward osteogenesis, while at the same time inhibiting adipogenic lineage commitment. Indeed, we observed reduced cellularity (Supplemental Figure S3) and adipogenesis (Figures 2 and 3) with NELL-1þBMP2 cotreatment compared with BMP2 treatment alone.…”

Brief Report: Human Perivascular Stem Cells and Nel-Like Protein-1 Synergistically Enhance Spinal Fusion in Osteoporotic Rats

“…There are several advantages to using NELL-1 in osteoporotic conditions over BMP-2: (1) NELL-1 inhibits BMP-2 induced inflammation by acting as an anti-inflammatory molecule [7]. (2) NELL-1 has anti-osteoclastic effects [25].…”

Effect of NELL1 gene overexpression in iPSC-MSCs seeded on calcium phosphate cement

“…For in vivo usage, superphysiological doses of the growth factors are usually needed in order to induce bone regeneration efficiently. For example, overdose of BMP2 could simultaneously cause potential side effects, such as inflammation, ectopic bone formation, and low quality of regenerated bone tissue with fatty marrow formed inside [11,12,15,55,56]. Therefore, it was necessary to find novel osteogenic growth factors for bone regeneration.…”