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.

Lef1 ablation alleviates cartilage mineralization following posttraumatic osteoarthritis induction

“…However, agonists of the WNT pathway were reported to either prevent OA ( 12 , 13 ) or adversely exacerbate OA ( 10 , 11 , 13 ). Similarly, in models of fracture repair, WNT activation promoted callus hypertrophy and repair ( 48 , 49 ); however, attempting to enhance WNT signaling by sclerostin-neutralizing antibodies did not expedite repair at advanced stages of fracture callus remodeling ( 50 ). Hence the role of WNT signaling in cartilage catabolism and mineralization remains elusive, indicating that this pathway is adversely regulated in chondrocytes and cartilage.…”

Circulating SIRT1 and Sclerostin Correlates with Bone Status in Young Women with Different Degrees of Adiposity

“…Mature osteoblasts then regulate bone remodeling processes under the influence of hormones and several growth factor signals [ 40 , 41 ]. Sclerostin inhibits osteoblast differentiation and, consequently, bone mineralization by interacting with the Wnt/β-catenin pathway, which represents one of the fundamental mechanisms of signaling that promotes cell proliferation, cell polarity and osteogenesis in humans [ 42 ]. Loss-of-function mutations in the SOST gene are associated with high bone mass [ 43 ], and the sclerostin antibody Romosozumab is a recently approved drug for the therapy of postmenopausal osteoporosis [ 44 ].…”

Recent Progresses in the Treatment of Osteoporosis

“…Delivery systems using peptides or chemicals with high affinity to bone are expected to overcome these drawbacks (Guan et al, 2012;Zur et al, 2018;Rammal et al, 2019). Bi-specific Wnt mimetic targeting both FZD and LRP has demonstrated a rapid and robust effect on bone building and correction of bone mass deficiency (Fowler et al, 2021), however, more studies are needed before preclinical and clinical trials of this agent. Besides, a cell/gene therapy in combination with miRNA manipulation may become effective treatment for osteoporosis.…”