The aging bone marrow microenvironment is characterized by chronic low-grade inflammation ("inflammaging"), which disrupts skeletal homeostasis and impairs bone regeneration. However, the stromal-immune crosstalk mechanisms sustaining this pathological state remain poorly defined. Here, transcriptomic analysis identified thrombospondin-1 (Thbs1) as a key upregulated component of the senescence-associated secretory phenotype (SASP) in aged bone mesenchymal stromal cells (BMSCs). We demonstrate that BMSC-derived Thbs1 drives pro-inflammatory M1 macrophage polarization by suppressing PINK1/Parkin-mediated mitophagy. Mechanistically, Thbs1 binds to the TGF-β type II receptor (Tgfbr2) on macrophages to activate Smad3 signaling, which transcriptionally represses the mitophagy regulator Pink1. This repression leads to mitochondrial superoxide accumulation and redox imbalance, thereby skewing macrophages toward an M1-like phenotype. These Thbs1-activated M1 macrophages, in turn, secrete IL-6, which activates the JAK/STAT3 pathway in BMSCs to inhibit osteogenic differentiation. Crucially, activated Stat3 directly binds the Thbs1 promoter, establishing a self-amplifying loop that perpetuates inflammaging and osteogenic decline. In vivo, AAV9-mediated Thbs1 knockdown in aged rat bone defects restored mitochondrial homeostasis, promoted an M2 macrophage transition, and significantly enhanced bone repair. Our study reveals a vicious cycle involving the Thbs1/TGF-β/Smad3/PINK1-IL-6/JAK/STAT3 axis that sustains inflammaging and osteogenic decline, highlighting Thbs1 as a promising therapeutic target for age-related bone regeneration.
Xing et al. (Mon,) studied this question.