New therapeutic target for osteoarthritis: modulating immune-metabolic aberrations and micromilieu remodeling in underlying bone

The Osteoimmunologic Basis of Biologic and Bioengineered Therapies in Osteoarthritis

Osteoarthritis (OA) is a significant clinical problem that places a substantial burden on both patients and the healthcare system. Characterized by progressive cartilage degeneration, synovial inflammation, and subchondral bone remodeling, OA is a rapidly growing and increasingly studied disease affecting millions around the world. Growing evidence has expanded on the traditional view of OA as a mechanical “wear-and-tear” disease, highlighting that disease progression is driven not only by mechanical stress but also by chronic dysregulation of the osteoimmune environment. Activation of innate and adaptive immune pathways, macrophage M1 polarization, and dysregulated cytokine signaling all contribute to progressive joint degeneration. While current therapeutics often focus on managing symptoms or restoring joint mechanics, interventions often overlook the role of osteoimmunology in disease progression. This review summarizes the biological and bioengineering strategies emerging to address OA. These platforms include bioceramics, metal-based scaffolds, hydrogels, nanoparticles, and microsphere systems. Furthermore, small molecules, cell-based therapies, and gene-modified systems have also been shown to modulate the inflammatory microenvironment, enhance regulatory immune responses, and restore cartilage homeostasis. Together, these approaches represent the evolving research landscape, shifting away from just symptom alleviation and towards targeted disease-modifying therapies, including osteoimmunomodulation. However, significant barriers to clinical translation remain, such as limited large animal studies and species immune system differences, which need to be addressed for the development of clinically applicable interventions.

Multifactorial Regulation of Inflammatory Bone Loss in Chronic Inflammatory and Immune-Associated Disorders: Osteoimmune Mechanisms and Translational Prospects of Natural Small Molecules

Advances in the study of the role of bone immunity in physiological and pathological processes related to bone metabolism.

BACKGROUND Bone metabolism is regulated by immune cells that maintain skeletal homeostasis through cytokine secretion and cell interactions. Disruption of this regulation-by inflammation, autoimmunity, or aging-drives pathological bone diseases including osteoporosis and rheumatoid arthritis. Single-cell technologies and exosome biology have revealed previously unrecognized immune subsets and regulatory layers within the bone microenvironment. MAIN BODY Osteoimmunology has elucidated the interplay between macrophages, T cells, B cells, NK cells, neutrophils, dendritic cells, and mast cells in bone remodeling. These cells form dynamic interaction networks-Treg-M2 feedback loops, Th17-neutrophil amplification, and B-T-osteoclast axes-that collectively determine net skeletal outcome. Immune cells regulate osteoclast and osteoblast function through TNF-α, IL-6, IL-17 A, and RANKL, with highly context-dependent effects. Immunosenescence has emerged as a key driver of age-related bone loss. The RANKL/RANK/OPG axis serves as the central signaling hub, modulated by Sema3A/Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch. Dysregulation of these pathways underlies osteoporosis, RA, intervertebral disc degeneration, ankylosing spondylitis, and cancer bone metastasis. Clinically, denosumab and cytokine-targeted biologics (anti-TNF-α, anti-IL-6R, anti-IL-17 A) demonstrate bone-protective effects, while bispecific antibodies, CAR-Treg cells, and senolytics represent emerging strategies. CONCLUSIONS The net skeletal effect of the immune system is determined by the balance of interacting cell types, cytokine networks, and signaling pathways. Future progress requires single-cell spatiotemporal multi-omics, cell-type-specific immunotherapies, elucidation of the gut-bone axis, and systematic evaluation of combination strategies pairing immunomodulators with anti-resorptives, anabolic agents, or senolytics.

Inflammaging and immunosenescence-driven remodeling of the immune microenvironment in osteoarthritis: mechanisms, immune regulation and immune reprogramming

It is highlighted that future OA treatment may gradually shift from symptom-oriented management toward disease-modifying therapy based on the identification of immune endotypes, and further studies are required to validate the underlying molecular mechanisms, evaluate safety, and conduct clinical trials, thereby facilitating the clinical translation of immune reprogramming strategies for OA.

Immune dysregulation in osteoarthritis: Mechanisms, biomarkers, and therapeutic opportunities

Osteoarthritis (OA) is increasingly recognized as a heterogeneous, immune-modulated joint disease in which chronic low-grade synovial inflammation contributes to structural degeneration and pain, challenging its historical classification as a purely mechanical disorder. Central to this paradigm shift is the recognition that synovial immune activation, particularly macrophage-driven inflammatory programs, is a key axis linking tissue damage to nociception and interacting with complementary inflammatory networks that collectively shape disease progression. However, translating these mechanistic insights into effective disease-modifying therapies has remained limited, with biologics targeting individual inflammatory mediators yielding inconsistent clinical benefit, thereby exposing a fundamental disconnect between molecular stratification and therapeutic response. This disconnect reflects the pronounced biological heterogeneity of OA, in which inflammatory activity is neither uniform nor temporally stable across disease stages. Emerging evidence supports the existence of distinct immunopathological endotypes, yet current therapeutic strategies remain largely unstratified and fail to account for this variability. Parallel advances in synovial biology and systems-level profiling have expanded the conceptual framework beyond single-cell pathways to encompass integrated immune-stromal interactions, but these insights have not yet translated into robust clinical decision-support tools. Therapeutically, multiple immune-modulatory approaches, including macrophage reprogramming, broader pathway modulation, and cellular or senescence-targeting strategies, have shown preclinical promise but remain constrained by limited clinical validation and inadequate patient selection frameworks. Across these approaches, a consistent barrier is the lack of reliable, reproducible biomarkers that link immunological heterogeneity to clinically actionable stratification. This review synthesizes current understanding of immune-driven mechanisms in OA, evaluates the translational performance of immunomodulatory interventions, and critically examines the limitations of existing biomarker strategies. It highlights the need for an integrated framework that links synovial immunobiology to endotype-specific patient classification, arguing that biomarker-guided stratification is a prerequisite for achieving precision immunomodulation and meaningful disease modification in OA.

Endocrine-metabolic imbalance drives osteoarthritis: From whole-joint pathobiology to precision therapy (Review)

Osteoarthritis (OA) is a chronic degenerative joint disease closely associated with aging and metabolic dysfunction, characterized by cartilage degeneration, synovial inflammation, aberrant subchondral bone remodeling, pain and progressive functional impairment. Beyond mechanical loading, accumulating evidence indicates that OA is increasingly recognized as a whole-joint disorder shaped by the interplay between local tissue damage and systemic endocrine-metabolic imbalance. Endocrine factors, including sex hormones, thyroid hormone, melatonin, parathyroid hormone and vitamin D, together with metabolic disturbances, such as obesity, insulin resistance, dysregulated glucose and lipid metabolism and gut microbiota imbalances, can cooperatively remodel the joint microenvironment. Mechanistically, these alterations converge on immuno-inflammatory amplification, mitochondrial dysfunction, oxidative stress, cellular senescence, metabolic reprogramming and regulated cell death, thereby promoting extracellular matrix degradation, persistent synovitis and uncoupled bone-cartilage remodeling. The present review systematically summarizes the molecular basis of endocrine-metabolic crosstalk in OA and discusses emerging therapeutic opportunities targeting hormonal signaling, metabolic pathways, circadian regulation, nutritional support and lifestyle interventions. Nevertheless, the reciprocal interactions among endocrine signals, systemic metabolic abnormalities and local joint pathology remain incompletely understood, and their translation into mechanism-based clinical stratification remains at an early stage. Thus, targeting endocrine-metabolic crosstalk may support mechanism-based phenotyping and subtype-informed precision therapy for OA, provided that candidate biomarkers and interventions are validated in prospective clinical studies.