A spatiotemporal atlas of senescence-associated secretory phenotype in fracture healing: stage-dependent mechanisms and therapeutic windows

Mar 31, 2026Inflammation and regeneration

Timing and location of aging-related cell signals during bone healing: stages and treatment opportunities

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

The senescence-associated secretory phenotype (SASP) may play distinct roles across the four phases of fracture healing.

During the inflammatory phase, SASP components enhance the recruitment of immune cells and initiate the fracture repair process.
In the soft-callus phase, SASP releases factors that promote the positioning of progenitor cells and support the formation of new blood vessels and cartilage.
The hard-callus phase is characterized by SASP factors that facilitate the conversion of cartilage to bone and early mineral deposition.
In the remodeling phase, SASP influences the balance between bone resorption and formation, where prolonged inflammation may disrupt proper remodeling.
The framework highlights that while transient SASP activation aids in repair, excessive or sustained SASP activity could impair bone healing.

AI simplified

Fracture repair remains a significant clinical challenge in orthopedics, particularly in aging populations. Accumulating evidence indicates that cellular senescence critically modulates the fracture microenvironment via the senescence-associated secretory phenotype (SASP). The SASP constitutes a complex secretory program of senescent cells that releases pro-inflammatory cytokines, growth factors, and matrix-modifying enzymes to reshape the surrounding microenvironment. Rather than being a random collection of molecules, the SASP represents a coordinated signaling network that can either promote tissue repair or drive chronic inflammation depending on its context. In this review, we apply a systematic SASP classification to the canonical four phases of fracture healing to clarify their distinct roles across these stages. During the inflammatory phase, SASP-associated (but non-exclusive) inflammatory cytokines and chemokines potentiate innate immune cell recruitment and early host defense, thereby initiating the repair cascade; in the soft-callus phase, chemotactic and angiogenic SASP components (such as CCL2, PDGF, VEGF) position mesenchymal progenitors and support chondrogenesis and neovascularization; in the hard-callus phase, osteoinductive growth factors and matrix-acting proteases (such as TGF-β, IGFBPs, MMP-9/13) promote cartilage-to-bone conversion and early mineral deposition; and in the remodeling phase, regulated SASP-mediated matrix changes couple osteoclast resorption with osteoblast formation, while sustained pro-inflammatory or profibrotic signals may hinder the fine remodeling of the structure. This stage-resolved framework elucidates the dual nature of SASP, with transient activation facilitating repair and sustained overproduction leading to impaired remodeling. This framework provides a conceptual basis for developing stage-specific interventions to enhance bone repair. Notably, many mediators discussed here overlap with the broader injury-induced inflammatory secretome and are not senescence-exclusive; where possible, we emphasize senescent-cell-enriched contributions and regulatory circuits rather than implying unique cellular origins.

Full Text

Full text is available at the source.

View full text (HTML) ↗

A spatiotemporal atlas of senescence-associated secretory phenotype in fracture healing: stage-dependent mechanisms and therapeutic windows

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief