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

  • Authors:
    • Ruhui Yang
    • Haimin Zeng
    • Qi Xiao
    • Yining Xie
    • Yi Long
    • Xiang Chen
  • View Affiliations / Copyright

    Affiliations: Department of Rehabilitation Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 252
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    Published online on: July 9, 2026
       https://doi.org/10.3892/ijmm.2026.5923
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Abstract

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.
View Figures

Figure 1

Systemic endocrine-metabolic network
driving OA. Sex hormones exert sex-specific effects. Physiological
estrogen acting through ERα/β supports chondrogenesis and type II
collagen synthesis and limits MMP-driven matrix degradation,
whereas the postmenopausal decline in estrogen is associated with a
higher risk of developing hand OA in women. Testosterone signaling
through the AR modulates bone metabolism and may influence OA risk
as well as pain and function in a sex-dependent manner. Thyroid
hormone signaling links systemic status to local joint regulation:
DIO2-mediated conversion of T4 to T3, followed by TRα activation,
promotes chondrocyte hypertrophic differentiation and extracellular
matrix breakdown; genetic and epidemiological evidence indicates
that higher FT4, together with derived indices such as the
FT3-to-FT4 ratio and TFQI, is associated with OA prevalence.
Circadian hormones are also integrated, highlighting
melatonin-mediated antioxidant and anti-inflammatory actions and
protection against cell death pathways including apoptosis and
ferroptosis, with potential analgesic benefits, whereas HPA-axis
cortisol shows heterogeneous, rhythm-dependent associations with
pain and inflammation. Additional endocrine inputs, including
parathyroid hormone, vitamin D and growth-factor signaling,
converge on cartilage metabolism and subchondral bone remodeling.
Metabolic OA pathways include obesity-related adipokines,
hyperglycemia and advanced glycation end products with insulin
resistance, lipid dysmetabolism and lipotoxicity and the gut-joint
axis. OA, osteoarthritis; ERα/β, estrogen receptor α/β; AR,
androgen receptor; MMP, matrix metalloproteinase; ECM,
extracellular matrix; HIF-2α, hypoxia-inducible factor-2α; RUNX2,
Runt-related transcription factor 2; T4, thyroxine
(tetraiodothyronine); T3, triiodothyronine; TRα, thyroid hormone
receptor alpha; DIO2, type 2 deiodinase; FT4, free thyroxine; FT3,
free triiodothyronine; TSH, thyroid-stimulating hormone; TFQI,
thyroid feedback quantile-based index; ROS, reactive oxygen
species; ER stress, endoplasmic reticulum stress; TNF-α, tumor
necrosis factor-α; IL-8, interleukin-8; HPA axis,
hypothalamic-pituitary-adrenal axis; GR, glucocorticoid receptor;
PTH, parathyroid hormone; AGEs, advanced glycation end products;
SCFAs, short-chain fatty acids. The figure was created in BioRender
(https://BioRender.com/cyuj626).

Figure 2

Immunometabolic stress links
endocrine-metabolic imbalance to chondrocyte degeneration in OA.
The image illustrates the convergence of hormonal and metabolic
stressors within chondrocytes, driving inflammatory amplification
and degenerative cell-fate transitions in OA. Upstream disturbances
include estrogen loss, impaired insulin signaling, dyslipidemia,
reduced GLP-1R signaling, gut microbiota dysbiosis, inflammatory
stimulation and mechanical stress. The schematic diagram is
organized from top to bottom into three conceptual layers: Signal
perception, stress integration and cellular outcomes. Extracellular
upstream stimuli are sensed by specific receptors on the cell
membrane. These signals converge intracellularly on two central,
interconnected stress hubs, mitochondrial dysfunction and NLRP3
inflammasome activation, which engage in a positive feedback loop.
This leads to the dysregulation of the central AMPK-mTOR axis and
disruption of autophagy flux. Ultimately, these integrated stresses
drive three major cell fate outcomes: Pyroptosis, ferroptosis and
cellular senescence. Ferroptosis is regulated in part by the system
Xc−/GSH/GPX4 axis and ROS/lipid peroxide accumulation,
whereas pyroptosis involves inflammasome activation, caspase-1 and
the release of IL-1β/IL-18. All three outcomes contribute to
amplifying the inflammatory response, thereby establishing a
chronic inflammatory feedback loop that exacerbates the initial
pathological state. OA, osteoarthritis; AMPK, AMP-activated protein
kinase; ERα/β, estrogen receptor α/β; GLP-1R, glucagon-like
peptide-1 receptor; GPX4, glutathione peroxidase 4; GPR, G
protein-coupled receptor; GSDMD, gasdermin D; IR, insulin receptor;
LOX-1, lectin-like oxidized low-density lipoprotein receptor-1;
MMP, matrix metalloproteinase; mTOR, mechanistic target of
rapamycin; NLRP3, NLR family pyrin domain-containing 3; SASP,
senescence-associated secretory phenotype; TLR4, Toll-like receptor
4; TNFR, tumor necrosis factor receptor. The figure was created in
BioRender (https://BioRender.com/x282hxr).

Figure 3

Therapeutic strategies targeting the
endocrine-metabolic axis in OA. These interventions modulate
inflammation, catabolic remodeling and cartilage integrity.
Lifestyle and circadian approaches, such as time-restricted eating
or intermittent fasting, enhance mitochondrial function and
autophagy, suppress inflammation and increase SCFAs. Melatonin
reduces ROS and lipid peroxidation, inhibits synovial inflammation
and angiogenesis and alleviates pain signaling. Metabolic
pathway-guided drug repurposing includes (A) glucagon-like
peptide-1 receptor agonists, which lower mechanical load and
pro-inflammatory cytokines and promote macrophage polarization from
M1 to M2; (B) metformin, which activates AMPK and SIRT1, enhances
mitophagy, suppresses senescence, and reduces matrix-degrading
enzymes; and (C) SGLT2 inhibitors, which activate SIRT1-dependent
autophagy, dampen endoplasmic reticulum stress and Hedgehog
signaling, reduce chondrocyte apoptosis and preserve type II
collagen. Hormone modulation, including hormone replacement therapy
and selective estrogen receptor modulators, exhibits timing- and
joint-dependent benefits, but carries systemic risks. Local
delivery approaches, including PRP + HA, chitosan plus low-dose
glucocorticoid, local growth hormone injection, lipid
nanoparticles, and liposome-anchored hydrogels, aim to prolong
joint retention and reduce systemic exposure. OA, osteoarthritis;
IF, intermittent fasting; NF-κB, nuclear factor kappa B; SCFAs,
short-chain fatty acids; ROS, reactive oxygen species; GLP-1,
glucagon-like peptide-1; GLP-1 RAs, glucagon-like peptide-1
receptor agonists; AMPK, AMP-activated protein kinase; SIRT1,
sirtuin 1; MMP, matrix metalloproteinase(s); ADAMTS, a disintegrin
and metalloproteinase with thrombospondin motifs; SGLT2,
sodium-glucose cotransporter 2; SGLT2i, sodium-glucose
cotransporter 2 inhibitor; ER, endoplasmic reticulum; HRT, hormone
replacement therapy; SERMs, selective estrogen receptor modulators;
PRP, platelet-rich plasma. The figure was created in BioRender
(https://BioRender.com/puoygvo).
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Spandidos Publications style
Yang R, Zeng H, Xiao Q, Xie Y, Long Y and Chen X: Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review). Int J Mol Med 58: 252, 2026.
APA
Yang, R., Zeng, H., Xiao, Q., Xie, Y., Long, Y., & Chen, X. (2026). Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review). International Journal of Molecular Medicine, 58, 252. https://doi.org/10.3892/ijmm.2026.5923
MLA
Yang, R., Zeng, H., Xiao, Q., Xie, Y., Long, Y., Chen, X."Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review)". International Journal of Molecular Medicine 58.3 (2026): 252.
Chicago
Yang, R., Zeng, H., Xiao, Q., Xie, Y., Long, Y., Chen, X."Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review)". International Journal of Molecular Medicine 58, no. 3 (2026): 252. https://doi.org/10.3892/ijmm.2026.5923
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Spandidos Publications style
Yang R, Zeng H, Xiao Q, Xie Y, Long Y and Chen X: Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review). Int J Mol Med 58: 252, 2026.
APA
Yang, R., Zeng, H., Xiao, Q., Xie, Y., Long, Y., & Chen, X. (2026). Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review). International Journal of Molecular Medicine, 58, 252. https://doi.org/10.3892/ijmm.2026.5923
MLA
Yang, R., Zeng, H., Xiao, Q., Xie, Y., Long, Y., Chen, X."Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review)". International Journal of Molecular Medicine 58.3 (2026): 252.
Chicago
Yang, R., Zeng, H., Xiao, Q., Xie, Y., Long, Y., Chen, X."Endocrine‑metabolic imbalance drives osteoarthritis: From whole‑joint pathobiology to precision therapy (Review)". International Journal of Molecular Medicine 58, no. 3 (2026): 252. https://doi.org/10.3892/ijmm.2026.5923
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