Bone-Targeted Delivery of Cell-Penetrating-RUNX2 Fusion Protein in Osteoporosis Model

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2023 Aug 13

PMID 37574255

Authors

Seoyeon Kim

Haein Lee

Jiyeon Hong

Seung Hyun L Kim

Euntaek Kwon

Tai Hyun Park

Nathaniel S Hwang

Affiliations

Soon will be listed here.

Abstract

The onset of osteoporosis leads to a gradual decrease in bone density due to an imbalance between bone formation and resorption. To achieve optimal drug efficacy with minimal side effects, targeted drug delivery to the bone is necessary. Previous studies have utilized peptides that bind to hydroxyapatite, a mineral component of bone, for bone-targeted drug delivery. In this study, a hydroxyapatite binding (HAB) tag is fused to 30Kc19α-Runt-related transcription factor 2 (RUNX2) for bone-targeting. This recombinant protein can penetrate the nucleus of human mesenchymal stem cells (hMSCs) and act as a master transcription factor for osteogenesis. The HAB tag increases the binding affinity of 30Kc19α-RUNX2 to mineral deposition in mature osteoblasts and bone tissue, without affecting its osteogenic induction capability. In the osteoporosis mouse model, intravenous injection of HAB-30Kc19α-RUNX2 results in preferential accumulation in the femur and promotes bone formation while reducing toxicity in the spleen. These findings suggest that HAB-30Kc19α-RUNX2 may be a promising candidate for bone-targeted therapy in osteoporosis.

Citing Articles

Development of Cytolytic Iridium-Complexed Octaarginine Peptide Albumin Nanomedicine for Hepatocellular Carcinoma Treatment.

Sun X, Wang D, Chang S, Yin L, Zhang H, Ji S Int J Nanomedicine. 2025; 20:2395-2409.

PMID: 40027874 PMC: 11871924. DOI: 10.2147/IJN.S502257.

Multi-omics Analysis to Identify Key Immune Genes for Osteoporosis based on Machine Learning and Single-cell Analysis.

Zhang B, Pei Z, Tian A, He W, Sun C, Hao T Orthop Surg. 2024; 16(11):2803-2820.

PMID: 39238187 PMC: 11541141. DOI: 10.1111/os.14172.

Epigallocatechin gallate protects MC3T3-E1 cells from cadmium-induced apoptosis and dysfunction via modulating PI3K/AKT/mTOR and Nrf2/HO-1 pathways.

Wei F, Lin K, Ruan B, Wang C, Yang L, Wang H PeerJ. 2024; 12:e17488.

PMID: 38827303 PMC: 11141548. DOI: 10.7717/peerj.17488.

Injectable ultrasound-powered bone-adhesive nanocomposite hydrogel for electrically accelerated irregular bone defect healing.

Zhou S, Xiao C, Fan L, Yang J, Ge R, Cai M J Nanobiotechnology. 2024; 22(1):54.

PMID: 38326903 PMC: 10851493. DOI: 10.1186/s12951-024-02320-y.

Liuwei Dihuang Pills Enhance Osteogenic Differentiation in MC3T3-E1 Cells through the Activation of the Wnt/β-Catenin Signaling Pathway.

Zhao J, Liang G, Yang J, Huang H, Dou Y, Gu Z Pharmaceuticals (Basel). 2024; 17(1).

PMID: 38256932 PMC: 10819701. DOI: 10.3390/ph17010099.

References

Khosla S, Hofbauer L . Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. 2017; 5(11):898-907. PMC: 5798872. DOI: 10.1016/S2213-8587(17)30188-2. View

Lee S, Park C, Han J, Kim J, Cho K, Kim E . Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2. Circ Res. 2016; 120(5):848-861. PMC: 5336520. DOI: 10.1161/CIRCRESAHA.116.309833. View

Ryu J, Hwang N, Park H, Park T . Protein-based direct reprogramming of fibroblasts to neuronal cells using 30Kc19 protein and transcription factor Ascl1. Int J Biochem Cell Biol. 2020; 121:105717. DOI: 10.1016/j.biocel.2020.105717. View

Kaur M, Nagpal M, Singh M . Osteoblast-n-Osteoclast: Making Headway to Osteoporosis Treatment. Curr Drug Targets. 2020; 21(16):1640-1651. DOI: 10.2174/1389450121666200731173522. View

Adelnia H, Tran H, Little P, Blakey I, Ta H . Poly(aspartic acid) in Biomedical Applications: From Polymerization, Modification, Properties, Degradation, and Biocompatibility to Applications. ACS Biomater Sci Eng. 2021; 7(6):2083-2105. DOI: 10.1021/acsbiomaterials.1c00150. View

Xiao G, Jiang D, Ge C, Zhao Z, Lai Y, Boules H . Cooperative interactions between activating transcription factor 4 and Runx2/Cbfa1 stimulate osteoblast-specific osteocalcin gene expression. J Biol Chem. 2005; 280(35):30689-96. DOI: 10.1074/jbc.M500750200. View

Liu J, Zeng Y, Shi S, Xu L, Zhang H, Pathak J . Design of polyaspartic acid peptide-poly (ethylene glycol)-poly (ε-caprolactone) nanoparticles as a carrier of hydrophobic drugs targeting cancer metastasized to bone. Int J Nanomedicine. 2017; 12:3561-3575. PMC: 5428813. DOI: 10.2147/IJN.S133787. View

Stapleton M, Sawamoto K, Almeciga-Diaz C, Mackenzie W, Mason R, Orii T . Development of Bone Targeting Drugs. Int J Mol Sci. 2017; 18(7). PMC: 5535838. DOI: 10.3390/ijms18071345. View

Jeong J, Kim J, Shim J, Hwang N, Heo C . Bioactive calcium phosphate materials and applications in bone regeneration. Biomater Res. 2019; 23:4. PMC: 6332599. DOI: 10.1186/s40824-018-0149-3. View

10.

Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K . Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997; 89(5):755-64. DOI: 10.1016/s0092-8674(00)80258-5. View

11.

Khadilkar S . Musculoskeletal Disorders and Menopause. J Obstet Gynaecol India. 2019; 69(2):99-103. PMC: 6430266. DOI: 10.1007/s13224-019-01213-7. View

12.

Kim S, Lee S, Son B, Kim J, Hwang N, Park T . Partially Digested Osteoblast Cell Line-Derived Extracellular Matrix Induces Rapid Mineralization and Osteogenesis. ACS Biomater Sci Eng. 2021; 7(3):1134-1146. DOI: 10.1021/acsbiomaterials.0c01349. View

13.

Ryu J, Kim H, Park H, Lee H, Park J, Rhee W . Protein-stabilizing and cell-penetrating properties of α-helix domain of 30Kc19 protein. Biotechnol J. 2016; 11(11):1443-1451. PMC: 5132017. DOI: 10.1002/biot.201600040. View

14.

Monnery B . Polycation-Mediated Transfection: Mechanisms of Internalization and Intracellular Trafficking. Biomacromolecules. 2021; 22(10):4060-4083. DOI: 10.1021/acs.biomac.1c00697. View

15.

Lee H, Park H, Kim J, Park J, Ryu J, Choi J . Enzyme delivery using the 30Kc19 protein and human serum albumin nanoparticles. Biomaterials. 2013; 35(5):1696-704. DOI: 10.1016/j.biomaterials.2013.11.001. View

16.

Kim H, Hong X, An Y, Park M, Kim D, Greene A . A Biphasic Osteovascular Biomimetic Scaffold for Rapid and Self-Sustained Endochondral Ossification. Adv Healthc Mater. 2021; 10(13):e2100070. PMC: 8273143. DOI: 10.1002/adhm.202100070. View

17.

Tu K, Lie J, Wan C, Cameron M, Austel A, Nguyen J . Osteoporosis: A Review of Treatment Options. P T. 2018; 43(2):92-104. PMC: 5768298. View

18.

Ducy P, Zhang R, Geoffroy V, Ridall A, Karsenty G . Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. 1997; 89(5):747-54. DOI: 10.1016/s0092-8674(00)80257-3. View

19.

Sophocleous A, Idris A . Rodent models of osteoporosis. Bonekey Rep. 2015; 3:614. PMC: 4388108. DOI: 10.1038/bonekey.2014.109. View

20.

Miller S, Pan H, Wang D, Bowman B, Kopeckova P, Kopecek J . Feasibility of using a bone-targeted, macromolecular delivery system coupled with prostaglandin E(1) to promote bone formation in aged, estrogen-deficient rats. Pharm Res. 2008; 25(12):2889-95. PMC: 2727931. DOI: 10.1007/s11095-008-9706-0. View