Sulfated polysaccharide prevents senescent adipocyte-driven osteonecrosis by stem cell fate reprogramming.

Excessive glucocorticoid (GC) administration is a major contributor to bone marrow senescence, which subsequently contributes to the development of osteonecrosis. Conventional therapeutic approaches have shown limited efficacy, largely because current interventions are typically initiated only after a definitive diagnosis of bone deterioration-by which time the disease has often progressed to an intermediate or advanced stage, thereby missing the optimal therapeutic window for effective intervention. Here, we report that a semi-synthetic sulfated chitosan (SCS) can effectively prevent the onset of GC-induced osteonecrosis by suppressing complete senescence of the bone marrow and maintaining coupling between arterial vascularization and osteogenesis. SCS attenuates the spread of GC-induced primary adipocyte senescence into secondary senescence, effectively limiting the progressive amplification of the senescence cascade. Rather than directly intervening in the prostaglandin/PPARγ/INK positive feedback loop within the senescent adipocyte lineage, SCS functions as an extracellular matrix component that activates the IGF-1/PI3K/Akt/mTOR signaling cascade. This activation reprograms the GC-induced lineage commitment bias of bone marrow leptin receptor+ (LepR+) mesenchymal stem cells (MSCs), leading to the downregulation of adipogenic differentiation and lipid biosynthesis pathways. By attenuating upstream senescence-driving cues at the source, SCS effectively suppresses the initiation and propagation of bone marrow adipocyte senescence. Thus, this highly bioactive polysaccharide halts the onset of senescence-driven osteonecrosis at an early stage, offering a promising avenue toward upstream, preventive interventions for skeletal aging and degeneration.