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Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation.
Biomaterials 2015; 67:308-22B

Abstract

Bone morphogenetic protein-2/absorbable collagen sponge (BMP-2/ACS) implants have been approved for clinical use to induce bone regeneration. We previously showed that exaggerated inflammation characterized by elevated level of inflammatory cytokines including TNF-α, IL-1β, and IL-6 has been shown to inhibit BMP-2/ACS-induced bone regeneration. Furthermore, unlike the negative effects of TNF-α and IL-1β, IL-6 seemed not to affect BMP-2-induced osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). We hypothesized that there may be a regulatory loop between IL-6 and BMP-2 singling to affect BMP-2/ACS-induced bone regeneration. Here, we established a BMP-2/ACS-induced ectopic bone formation model in rats and fund that IL-6 injection significantly increased BMP-2/ACS-induced bone mass. Consistent with this animal model, an in vitro study demonstrated that synergy between IL-6 and soluble IL-6 receptor (IL-6/sIL-6R) promotes BMP-2-induced osteoblastic differentiation of human BMSCs through amplification of BMP/Smad signaling. Strikingly, IL-6 injection did not activate osteoclast-mediated bone resorption in the ectopic bone formation model, and IL-6/sIL-6R treatment did not affect receptor activator of NF-κB ligand (RANKL)-induced osteoclastic differentiation of human peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, IL-6/sIL-6R treatment did not affect expression of BMP receptors, but enhanced the cell surface translocation of BMP receptor IA (BMPRIA) and inhibited the degradation of BMPRIA. Collectively, these findings indicate that synergy between IL-6 and sIL-6R promotes the cell surface translocation of BMPRIA and maintains the stability of BMPRIA expression, leading to enhanced BMP-2/ACS-induced bone regeneration.

Authors+Show Affiliations

Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.Department of General, Trauma, Hand, and Plastic Surgery, University of Munich, Munich, Germany.Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China. Electronic address: dr.liqingfeng@shsmu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26232880

Citation

Huang, Ru-Lin, et al. "Synergy Between IL-6 and Soluble IL-6 Receptor Enhances Bone Morphogenetic Protein-2/absorbable Collagen Sponge-induced Bone Regeneration Via Regulation of BMPRIA Distribution and Degradation." Biomaterials, vol. 67, 2015, pp. 308-22.
Huang RL, Chen G, Wang W, et al. Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation. Biomaterials. 2015;67:308-22.
Huang, R. L., Chen, G., Wang, W., Herller, T., Xie, Y., Gu, B., & Li, Q. (2015). Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation. Biomaterials, 67, pp. 308-22. doi:10.1016/j.biomaterials.2015.07.047.
Huang RL, et al. Synergy Between IL-6 and Soluble IL-6 Receptor Enhances Bone Morphogenetic Protein-2/absorbable Collagen Sponge-induced Bone Regeneration Via Regulation of BMPRIA Distribution and Degradation. Biomaterials. 2015;67:308-22. PubMed PMID: 26232880.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergy between IL-6 and soluble IL-6 receptor enhances bone morphogenetic protein-2/absorbable collagen sponge-induced bone regeneration via regulation of BMPRIA distribution and degradation. AU - Huang,Ru-Lin, AU - Chen,Gang, AU - Wang,Wenjin, AU - Herller,Tanja, AU - Xie,Yun, AU - Gu,Bin, AU - Li,Qingfeng, Y1 - 2015/07/26/ PY - 2015/04/11/received PY - 2015/07/22/revised PY - 2015/07/23/accepted PY - 2015/8/3/entrez PY - 2015/8/4/pubmed PY - 2016/5/24/medline KW - BMP-2 KW - BMPRIA KW - Bone regeneration KW - Cell surface translocation KW - IL-6 KW - sIL-6R SP - 308 EP - 22 JF - Biomaterials JO - Biomaterials VL - 67 N2 - Bone morphogenetic protein-2/absorbable collagen sponge (BMP-2/ACS) implants have been approved for clinical use to induce bone regeneration. We previously showed that exaggerated inflammation characterized by elevated level of inflammatory cytokines including TNF-α, IL-1β, and IL-6 has been shown to inhibit BMP-2/ACS-induced bone regeneration. Furthermore, unlike the negative effects of TNF-α and IL-1β, IL-6 seemed not to affect BMP-2-induced osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs). We hypothesized that there may be a regulatory loop between IL-6 and BMP-2 singling to affect BMP-2/ACS-induced bone regeneration. Here, we established a BMP-2/ACS-induced ectopic bone formation model in rats and fund that IL-6 injection significantly increased BMP-2/ACS-induced bone mass. Consistent with this animal model, an in vitro study demonstrated that synergy between IL-6 and soluble IL-6 receptor (IL-6/sIL-6R) promotes BMP-2-induced osteoblastic differentiation of human BMSCs through amplification of BMP/Smad signaling. Strikingly, IL-6 injection did not activate osteoclast-mediated bone resorption in the ectopic bone formation model, and IL-6/sIL-6R treatment did not affect receptor activator of NF-κB ligand (RANKL)-induced osteoclastic differentiation of human peripheral blood mononuclear cells (PBMCs) in vitro. Furthermore, IL-6/sIL-6R treatment did not affect expression of BMP receptors, but enhanced the cell surface translocation of BMP receptor IA (BMPRIA) and inhibited the degradation of BMPRIA. Collectively, these findings indicate that synergy between IL-6 and sIL-6R promotes the cell surface translocation of BMPRIA and maintains the stability of BMPRIA expression, leading to enhanced BMP-2/ACS-induced bone regeneration. SN - 1878-5905 UR - https://www.unboundmedicine.com/medline/citation/26232880/Synergy_between_IL_6_and_soluble_IL_6_receptor_enhances_bone_morphogenetic_protein_2/absorbable_collagen_sponge_induced_bone_regeneration_via_regulation_of_BMPRIA_distribution_and_degradation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0142-9612(15)00635-3 DB - PRIME DP - Unbound Medicine ER -