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Development of selective bispecific Wnt mimetics for bone loss and repair.

ABSTRACT: The Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency and bone defects in various disease models, including osteoporosis, aging, and long bone fracture. Furthermore, when these Wnt agonists are combined with antiresorptive bisphosphonates or anti-sclerostin antibody therapies, additional bone accrual/maintenance effects are observed compared to monotherapy, which could benefit individuals with severe and/or acute bone-building deficiencies. Our data support the continued development of Wnt mimetics for the treatment of diseases of low bone mineral density, including osteoporosis.

SUBMITTER: Fowler TW

PROVIDER: S-EPMC8167098 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Development of selective bispecific Wnt mimetics for bone loss and repair.

Fowler Tristan W TW Mitchell Troy L TL Janda Claudia Y CY Xie Liqin L Tu Shengjiang S Chen Hui H Zhang Haili H Ye Jingjing J Ouyang Brian B Yuan Tom Z TZ Lee Sung-Jin SJ Newman Maureen M Tripuraneni Nikita N Rego Erica S ES Mutha Devin D Dilip Archana A Vuppalapaty Meghah M Baribault Helene H Yeh Wen-Chen WC Li Yang Y

Nature communications 20210531 1

The Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency an ...[more]

PMID: 34059688

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Project description:There is a continuing need for artificial bone substitutes for bone repair and reconstruction, Magnesium phosphate bone cement (MPC) has exceptional degradable properties and exhibits promising biocompatibility. However, its mechanical strength needs improved and its low osteo-inductive potential limits its therapeutic application in bone regeneration. We functionally modified MPC by using a polymeric carboxymethyl chitosan-sodium alginate (CMCS/SA) gel network. This had the advantages of: improved compressive strength, ease of handling, and an optimized interface for bioactive bone in-growth. The new composites with 2% CMCS/SA showed the most favorable physicochemical properties, including mechanical strength, wash-out resistance, setting time, injectable time and heat release. Biologically, the composite promoted the attachment and proliferation of osteoblast cells. It was also found to induce osteogenic differentiation in vitro, as verified by expression of osteogenic markers. In terms of molecular mechanisms, data showed that new bone cement activated the Wnt pathway through inhibition of the phosphorylation of β-catenin, which is dependent on focal adhesion kinase. Through micro-computed tomography and histological analysis, we found that the MPC-CMCS/SA scaffolds, compared with MPC alone, showed increased bone regeneration in a rat calvarial defect model. Overall, our study suggested that the novel composite had potential to help repair critical bone defects in clinical practice. Graphical abstract Image 1 Highlights • CMCS/SA improves the mechanical strength of MPC while minimizing tissue damage.• The MPC-CMCS/SA composite is easily manipulable for clinical application.• MPC-CMCS/SA has good biocompatibility, and is easier for cell adhesion and proliferation.• The MPC-CMCS/SA composite enhances osteogenic differentiation in vitro through the integrin-FAK-Wnt axis.• The MPC-CMCS/SA composite enhances critical bone defect repair in vivo.

Dataset Information

Development of selective bispecific Wnt mimetics for bone loss and repair.

Publications

Development of selective bispecific Wnt mimetics for bone loss and repair.

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