Regulating macrophage-MSC interaction to optimize BMP-2-induced osteogenesis in the local microenvironment

Fei Jiang; Xuanyu Qi; Xiaolin Wu; Sihan Lin; Junfeng Shi; Wenjie Zhang; Xinquan Jiang

doi:10.1016/j.bioactmat.2023.02.001

Regulating macrophage-MSC interaction to optimize BMP-2-induced osteogenesis in the local microenvironment

Bioact Mater. 2023 Feb 11:25:307-318. doi: 10.1016/j.bioactmat.2023.02.001. eCollection 2023 Jul.

Authors

Fei Jiang^{1

2

3

4}, Xuanyu Qi^{1

2}, Xiaolin Wu^{1

2}, Sihan Lin^{1

2}, Junfeng Shi^{1

2}, Wenjie Zhang^{1

2}, Xinquan Jiang^{1

2}

Affiliations

¹ Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No.639, Zhizaoju Road, Shanghai, 200011, China.
² College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, No.639, Zhizaoju Road, Shanghai, 200011, China.
³ Jiangsu Key Laboratory of Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, No. 140, Han Zhong Road, Nanjing, 210029, China.
⁴ Department of General Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, No. 136, Han Zhong Road, Nanjing, 210029, China.

Abstract

Bone morphogenetic protein (BMP-2) has been approved by the FDA to promote bone regeneration, but uncertain osteogenic effect and dose-dependent side effects may occur. Osteoimmunomodulation plays an important role in growth factor-based osteogenesis. Here, we explored how proinflammatory signals affect the dose-dependent osteogenic potential of BMP-2. We observed that the expression level of local IL-1β did not increase with the dose of BMP-2 in the mouse osteogenesis model. A low dose of BMP-2 could not promote new bone formation, but trigger the release of IL-1β from M1 macrophages. As the dose of BMP-2 increased, the IL-1β expression and M1 infiltration in local microenvironment were inhibited by IL-1Ra from MSCs under osteogenic differentiation induced by BMP-2, and new bone tissues formed, even excessively. Anti-inflammatory drugs (Dexamethasone, Dex) promoted osteogenesis via inhibiting M1 polarization and enhancing BMP-2-induced MSC osteo-differentiation. Thus, we suggest that the osteogenic effect of BMP-2 involves macrophage-MSC interaction that is dependent on BMP-2 dose and based on IL-1R1 ligands, including IL-1β and IL-1Ra. The dose of BMP-2 could be reduced by introducing immunoregulatory strategies.

Keywords: BMP-2; IL-1Ra; IL-1β; Macrophage-MSC interaction; Osteogenesis.