Work

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

Year: 2026

Type: article

Abstract: 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. • Excess GC targets adipocytes, triggering prostaglandin/PPARγ/INK signaling. The resulting senescence leads to osteonecrosis. • SCS limits the spread of primary adipocyte senescence to secondary forms, restraining further senescence amplification. • SCS reprograms the lineage commitment bias of LepR + MSCs by activating the IGF-1/PI3K/Akt/mTOR signaling cascade.

Source: Bioactive Materials

DOI: 10.1016/j.bioactmat.2025.11.039

Authors: Shuang Zhang, Shunshu Deng, Kai Dai, Yang Liu, Jing Wang, Changsheng Liu

Institutions: East China University of Science and Technology, State Key Laboratory of Bioreactor Engineering, Fudan University, Eye & ENT Hospital of Fudan University

Language: English

Topic: Bone and Joint Diseases

Subfield: Orthopedics and Sports Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,200