Immunosenescence remodels the osteoimmune microenvironment in osteoarthritis: from cellular crosstalk to regenerative therapeutics
Abstract
Osteoarthritis (OA) has evolved from a condition conventionally regarded as mere mechanical “wear and tear” to a complex, whole-joint disorder driven by chronic low-grade inflammation and cellular dysfunction. Within the joint, the osteoimmune microenvironment—composed of articular cartilage, synovium, subchondral bone, the infrapatellar fat pad (IPFP), and resident stem cell niches—serves as the central site of osteoimmune interaction for maintaining tissue homeostasis and repair. Accumulating evidence indicates that age-associated dysregulation and senescence of innate and adaptive immune cell subsets represent major contributors to OA progression. Age- and senescence-associated immune states generate persistent inflammatory, oxidative, and damage-associated signals that contribute to microenvironmental deterioration. In this review, we propose a unified framework elucidating how immunosenescence reshapes the osteoimmune microenvironment via aberrant intercellular communication. We systematically delineate the distinct cellular crosstalk networks connecting immunosenescent drivers with chondrocytes, synovial fibroblasts, subchondral bone remodeling units, IPFP adipocytes, and mesenchymal stem/stromal cells (MSCs). Furthermore, we highlight emerging therapeutic avenues to reprogram this senescent niche, encompassing senotherapeutics, immunometabolic reprogramming, biomaterial-assisted targeted delivery, and engineered cell therapies. Finally, we propose the “Resolution Failure Hypothesis” as a testable mechanistic framework in which impaired efferocytosis and dysregulated specialized pro-resolving mediator (SPM) signaling may contribute to the persistence of osteoimmune remodeling. Rather than proposing defective inflammation resolution as a new biological phenomenon, this framework integrates established resolution-related mechanisms with age-associated immune remodeling and asks whether insufficient restoration of clearance and resolution capacity helps explain the incomplete structural recovery observed after senescent-cell-targeted interventions. Reconceptualizing OA through the lens of immunosenescent crosstalk will accelerate the translation of disease-modifying therapies from microenvironmental modulation toward functional joint regeneration.
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BibTeX
@article{liu2026immunosenescence,
title = {{Immunosenescence remodels the osteoimmune microenvironment in osteoarthritis: from cellular crosstalk to regenerative therapeutics}},
author = {Ruofan Liu and Ziheng Zhu and Yunfei Li and Xiaoman Xing and Xinyang Wang and Chuanbing Huang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1976649},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1976649},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immunosenescence remodels the osteoimmune microenvironment in osteoarthritis: from cellular crosstalk to regenerative therapeutics
AU - Ruofan Liu
AU - Ziheng Zhu
AU - Yunfei Li
AU - Xiaoman Xing
AU - Xinyang Wang
AU - Chuanbing Huang
PY - 2026
DA - 2026/10/30
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1976649
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1976649
AB - Osteoarthritis (OA) has evolved from a condition conventionally regarded as mere mechanical “wear and tear” to a complex, whole-joint disorder driven by chronic low-grade inflammation and cellular dysfunction. Within the joint, the osteoimmune microenvironment—composed of articular cartilage, synovium, subchondral bone, the infrapatellar fat pad (IPFP), and resident stem cell niches—serves as the central site of osteoimmune interaction for maintaining tissue homeostasis and repair. Accumulating evidence indicates that age-associated dysregulation and senescence of innate and adaptive immune cell subsets represent major contributors to OA progression. Age- and senescence-associated immune states generate persistent inflammatory, oxidative, and damage-associated signals that contribute to microenvironmental deterioration. In this review, we propose a unified framework elucidating how immunosenescence reshapes the osteoimmune microenvironment via aberrant intercellular communication. We systematically delineate the distinct cellular crosstalk networks connecting immunosenescent drivers with chondrocytes, synovial fibroblasts, subchondral bone remodeling units, IPFP adipocytes, and mesenchymal stem/stromal cells (MSCs). Furthermore, we highlight emerging therapeutic avenues to reprogram this senescent niche, encompassing senotherapeutics, immunometabolic reprogramming, biomaterial-assisted targeted delivery, and engineered cell therapies. Finally, we propose the “Resolution Failure Hypothesis” as a testable mechanistic framework in which impaired efferocytosis and dysregulated specialized pro-resolving mediator (SPM) signaling may contribute to the persistence of osteoimmune remodeling. Rather than proposing defective inflammation resolution as a new biological phenomenon, this framework integrates established resolution-related mechanisms with age-associated immune remodeling and asks whether insufficient restoration of clearance and resolution capacity helps explain the incomplete structural recovery observed after senescent-cell-targeted interventions. Reconceptualizing OA through the lens of immunosenescent crosstalk will accelerate the translation of disease-modifying therapies from microenvironmental modulation toward functional joint regeneration.
SN - 1664-3224
ER -