高分子量聚谷氨酸改善BMP2诱导的成骨分化《Molecular Pharmaceutics》

High Molecular Weight Poly(glutamic acid) to Improve BMP2-Induced Osteogenic Differentiation

Jue Hu, Zhuozhi Wang, Jacob M. Miszuk, Erliang Zeng, and Hongli Sun*

Department of Oral and Maxillofacial Surgery, University of Iowa College of Dentistry, Iowa City, Iowa 52242, United States

Iowa Institute for Oral Health Research, University of Iowa College of Dentistry, Iowa City, Iowa 52242, United States

Mol. Pharmaceutics 2022, XXXX, XXX, XXX-XXX

Publication Date: June 8, 2022

https://doi.org/10.1021/acs.molpharmaceut.2c00141

Abstract

FDA-approved bone morphogenetic protein 2 (BMP2) has serious side effects due to the super high dose requirement. Heparin is one of the most well-studied sulfated polymers to stabilize BMP2 and improve its functionality. However, the clinical use of heparin is questionable because of its undesired anticoagulant activity. Recent studies suggest that poly(glutamic acid) (pGlu) has the potential to improve BMP2 bioactivity with less safety concerns; however, the knowledge on pGlu’s contribution remains largely unknown. Therefore, we aimed to study the role of pGlu in BMP2-induced osteogenesis and its potential application in bone tissue engineering. Our data, for the first time, indicated that both low (L-pGlu) and high molecular weight pGlu (H-pGlu) were able to significantly improve the BMP2-induced early osteoblastic differentiation marker (ALP) in MC3T3-E1 preosteoblasts. Importantly, the matrix mineralization was more rapidly enhanced by H-pGlu compared to L-pGlu. Additionally, our data indicated that only α-H-pGlu could significantly improve BMP2’s activity, whereas γ-H-pGlu failed to do so. Moreover, both gene expression and mineralization data demonstrated that α-H-pGlu enabled a single dose of BMP2 to induce a high level of osteoblastic differentiation without multiple doses of BMP2. To study the potential application of pGlu in tissue engineering, we incorporated the H-pGlu+BMP2 nanocomplexes into the collagen hydrogel with significantly elevated osteoblastic differentiation. Furthermore, H-pGlu-coated 3D porous gelatin and chitosan scaffolds significantly enhanced osteogenic differentiation through enabling sustained release of BMP2. Thus, our findings suggest that H-pGlu is a promising new alternative with great potential for bone tissue engineering applications.

KEYWORDS:

• poly(glutamic acid)

• bone morphogenetic protein-2

• drug release

• osteogenic differentiation

• 3D porous scaffold

• bone tissue engineering

SUBJECTS:

• Biopolymers,

• Coating materials,

• Hydrogels,

• Mineralization,

• Scaffolds