BACKGROUND CONTEXT: BMP-2 has been used to successfully promote spine fusion, but side effect including nerve inflammation have been observed. PURPOSE: Investigate the direct neurotoxic effects of BMP-2 and test the hypotheses that the use of BMP binding proteins, such as secreted phosphoprotein 24 kD (Spp24), can reduce or eliminate these effects. STUDY DESIGN: In vitro experiments and in vivo analysis in a rodent model. METHODS: In vitro, dorsal root ganglion cells were cultured in the presence of BMP-2 with and without Spp24 and CGRP and Substance P, markers of neuro-inflammation, were measured by immunohistochemistry. In vivo, rats underwent a left sided laminotomy at L5 to expose the S1 nerve root and were randomized into four different groups according to the intervention at the laminotomy site: 1) collagen sponge only (no BMP-2 or Spp24), 2) BMP-2 in a collagen sponge only, 3) BMP-2 in a collagen sponge + an empty collagen sponge to act as a barrier, 4) BMP-2 in a collagen sponge + Spp24 in a collagen sponge to act as a barrier. Functional evaluation was done using the Basso, Beattie and Bresnahan scale and immunohistochemical analyses was performed using CGRP and Substance P staining. This study was supported by a $25,000 grant from Cervical Spine Research Society, and all the disclosed conflict of interests should have no influence on the accuracy of the data being reported. RESULTS: The neuro-inflammatory effects of BMP-2 in vitro were ameliorated by the addition of Spp24. Similarly, in vivo, Spp24 reduced the expression of markers on neuro-inflammation in animals treated with BMP-2 and also improved function after BMP-2 administration. CONCLUSIONS: These results confirm that BMP binding proteins have great potential as adjuvant therapies to limit BMP-2 related side effects in spine surgery.