High Doses of Bone Morphogenetic Protein 2 Induce Structurally Abnormal Bone and Inflammation <i>In Vivo</i>

TLDR

BMPs are FDA‑approved osteoinductive factors widely used clinically, yet they can cause adverse effects such as cyst‑like bone formation and soft tissue swelling. The study aimed to evaluate the dose‑dependent effects of BMP2 in rat femoral defect and onlay models. Researchers administered varying BMP2 concentrations (low, mid, high) in a rat femoral segmental defect and minimally traumatic onlay model to assess fusion and adverse outcomes. Low doses failed to fuse defects, mid‑range doses fused without adverse effects, while high doses fused but produced cyst‑like bone shells with adipose tissue and induced significant inflammation and osteoclast‑like cells, mirroring human high‑dose side effects.

Abstract

The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.