Fracture healing: from molecular and cellular mechanisms to therapeutic strategies.

Authors

Flurina Staubli, Renske Maria Tariro Ten Ham, Jan Eelco Bergsma, Debby Gawlitta, Kenny Man

Published in

Signal transduction and targeted therapy. Volume 11. Issue 1. Sep 22, 2026. Epub Sep 22, 2026.

Abstract

Fracture healing is a highly orchestrated regenerative process that depends on precise temporal and spatial coordination of immune, vascular, neural, and skeletal signaling programs. Disruption of these interconnected pathways, whether due to local injury factors, systemic disease, aging, or metabolic dysregulation, can impair repair and result in delayed union or nonunion. Understanding the molecular mechanisms that integrate inflammation resolution, progenitor cell fate decisions, neurovascular coupling, and endochondral bone formation is therefore essential for improving clinical outcomes. Recent advances show that fracture repair is governed by dynamic signaling networks linking immune cells, mesenchymal progenitors, endothelial and neural components, and the extracellular matrix. Key pathways regulating cytokine signaling, angiogenesis, mechanotransduction, hypoxia sensing, and osteochondral differentiation have emerged as critical determinants of healing efficiency and quality. These insights have reshaped therapeutic strategies, enabling the development of targeted interventions, including growth factor and anabolic therapies, immunomodulatory agents, cell- and gene-based approaches, extracellular vesicles, and biomaterial-assisted delivery systems. In this review, we synthesize current mechanistic understanding of both physiological and impaired fracture healing, with an emphasis on intercellular signaling and pathway-level regulation. We critically evaluate emerging targeted regenerative therapies in terms of their biological rationale, precision, and translational limitations, and discuss key barriers to clinical implementation. By shifting focus from descriptive pathology to actionable signaling frameworks, this review aims to guide the rational design of next-generation therapies for bone regeneration.

PMID:
42768017
Bibliographic data and abstract were imported from PubMed on 22 Sep 2026.

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