Targeting strategies for bone diseases: signaling pathways and clinical studies

Abstract

Since the proposal of Paul Ehrlich’s magic bullet concept over 100 years ago, tremendous advances have occurred in targeted therapy. From the initial selective antibody, antitoxin to targeted drug delivery that emerged in the past decades, more precise therapeutic efficacy is realized in specific pathological sites of clinical diseases. As a highly pyknotic mineralized tissue with lessened blood flow, bone is characterized by a complex remodeling and homeostatic regulation mechanism, which makes drug therapy for skeletal diseases more challenging than other tissues. Bone-targeted therapy has been considered a promising therapeutic approach for handling such drawbacks. With the deepening understanding of bone biology, improvements in some established bone-targeted drugs and novel therapeutic targets for drugs and deliveries have emerged on the horizon. In this review, we provide a panoramic summary of recent advances in therapeutic strategies based on bone targeting. We highlight targeting strategies based on bone structure and remodeling biology. For bone-targeted therapeutic agents, in addition to improvements of the classic denosumab, romosozumab, and PTH1R ligands, potential regulation of the remodeling process targeting other key membrane expressions, cellular crosstalk, and gene expression, of all bone cells has been exploited. For bone-targeted drug delivery, different delivery strategies targeting bone matrix, bone marrow, and specific bone cells are summarized with a comparison between different targeting ligands. Ultimately, this review will summarize recent advances in the clinical translation of bone-targeted therapies and provide a perspective on the challenges for the application of bone-targeted therapy in the clinic and future trends in this area.

Cichoric acid targets RANKL to inhibit osteoclastogenesis and prevent ovariectomy‐induced bone loss

“…However, these drugs produce complex and varied adverse effects in treatment, so the search for targeted osteoclast drugs to treat osteoporosis has been a hot issue (Cotts & Cifu, 2018). RANKL, a protein encoded by the Tnfsf11 gene, is necessary for osteoclasts to resorb bone in both physiological and pathological conditions (Bae et al, 2023;McDonald et al, 2021;Xu et al, 2023). Osteoblast-lineage cells release RANKL, which binds to its receptor RANK on the surface of myeloid cells, promoting osteoclast differentiation (Li, Wang, et al, 2022;Uenaka et al, 2022).…”

Fluorinated hydroxyapatite conditions a favorable osteo-immune microenvironment via triggering metabolic shift from glycolysis to oxidative phosphorylation

“…The aforementioned findings from the present study suggested that FPHA had the ability to suppress the M1 polarization of macrophages while promoting their polarization toward the M2 phenotype, leading to the creation of a favorable osteo-immune microenvironment. Bone remodeling is intricately and spatiotemporally regulated by the balance between osteoclast-mediated resorption and osteoblast-mediated formation [ 37 ]. Therefore, we cultured rBMSCs in a co-stimulation medium to evaluated the effect of FPHA on osteogenesis.…”

TAM receptors control actomyosin dynamics in osteoclasts via RHOA-COFILIN-MYOSIN II signaling

“…In clinical practice, osteoclast targeting agents mostly consist of bisphosphonates and denosumab 26 . Routinely used bisphosphonates such as alendronate, pamidronate and zoledronic acid have a nitrogen group which blocks the activity of farnesyl diphosphate synthase (FDPS) thereby inhibiting the prenylation of small GTPases such as RAS, RHOA and RAC1 which are critical signaling mediators for maintaining the osteoclast cytoskeleton 27 . Denosumab is a human monoclonal antibody against RANKL 26 .…”