Table 1.

Studies reported that IFN-γ mediates the occurrence and development of osteoporosis by affecting bone remodeling.

Author/Year	Diseases/Animal modal/Cell model	Main function
Fawaz Y Azizieh et al./2019 (131)	Healthy, osteopenic and osteoporotic postmenopausal women.	In postmenopausal women, osteoporosis serum levels of IFN-γ, IL-12p70, IL-33, IFN-α2, and MCP-1 were significantly elevated.
Bolaji Lilian Ilesanmi-Oyelere et al./2019 (132)	86 menopausal women were categorized into three groups: healthy, osteopenic and osteoporotic.	The levels of cytokines (IFN-γ, IFNα2, IL-33, IL-12p70, IL-12p70) and MCP-1 in plasma were significantly higher in the osteoporosis group.
V Breuil et al./2010 (133)	26 postmenopausal women with osteoporosis and 24 healthy women.	Postmenopausal osteoporotic women exhibit significantly reduced IFN-γ secretion by CD4+ T lymphocytes.
Wei Zhang et al./2022 (134)	Healthy, osteopenic and osteoporotic elderly male.	Elderly male patients with osteoporosis had higher expression of RANKL/OPG, TNF-α, IL-6, and lower expression of IFN-γ and IL-10.
Cong Peng et al./2022 (135)	20 elderly osteoporotic patients and 20 non-osteoporotic healthy individuals.	IFN-γ levels were significantly lower in elderly patients with osteoporosis.
Tiago Azenha Rama et al./2023 (136)	Systemic Mastocytosis patients (n=120) were categorized according to their bone status: healthy bone, osteoporosis and diffuse osteosclerosis.	In osteoporosis patients, there is a notable elevation in serum baseline levels of tryptase, IFN-γ, IL-1β, and IL-6.
Roba M Talaat et al./2015 (137)	20 osteopenic and 20 osteoporotic patients treated with bisphosphonates.	In treated osteoporosis patients, there was a significant decrease in plasma levels of IFN-γ, IL-17, IL-23, and IL-6.
Simone Cenci et al./2003 (138)	IFN-γR knock-out mice and their WT littermates; ovariectomized and sham-operated mice.	In estrogen-deficient conditions, the induction of CIITA by IFN-γ escalates antigen-presenting cell (APC) activity and T-cell proliferation. This process contributes to the expansion of the T-cell pool, heightened TNF production, and the in vivo occurrence of TNF-induced bone loss.
Yuhao Gao et al./2007 (139)	IFN-γR knock-out mice and their WT littermates; ovariectomized and sham-operated mice.	The activation and proliferation of antigen-dependent T-cells driven by IFN-γ, along with elevated concentrations of RANKL and TNF-α, foster osteoclastogenesis, ultimately resulting in a net loss of bone tissue.
L Wang et al./2015 (140)	Ovariectomy-induced osteoporotic mice and sham-operated mice; FASL-null mice and their littermates; IFN-γ knockout mice and their littermates.	Administration of IFN-γ to OVX-induced osteoporotic mice ameliorated the osteoporotic phenotype and increased the expression of FASL in osteoblasts, promoting osteoclast apoptosis and inhibiting bone resorption.
Gustavo Duque et al./2011 (141)	IFN-γR knock-out mice and their littermates; OVX-induced osteoporotic mice and sham-operated mice.	Compared with IFNγR1(+/+) mice, IFNγR1(-/-) mice had reduced bone mass and bone mineral density and exhibited significant osteoporotic features. In addition, administration of IFN-γ to OVX female mice significantly improved bone remodeling, bone mechanical properties, bone microarchitecture, and bone mass, and ameliorated osteoporosis in OVX mice.
Miyuki Tsumura et al./2022 (142)	Patients with autosomal dominant (AD) IFN-γR1 deficiency.	Patients with AD IFN-γR1 deficiency have an increased proportion of GM colonies differentiating into osteoclasts in response to RANKL and M-CSF. IFN-γ concentration-dependent inhibition of osteoclast formation is impaired.
Elena V Shashkova et al./2016 (143)	IFN-γR knock-out mice and their littermates.	TcREG inhibits actin reorganization and osteoclast attachment to the bone matrix by blocking the αvβ3 signaling of IFN-γ, which ultimately inhibits bone resorption.
Masatsugu Komagamine et al./2023 (144)	Collagen-induced arthritis (CIA) mice	JAK inhibitors reduce the number of osteoclasts and ameliorate systemic bone loss. JAK inhibitors attenuate the inhibitory effect of Th1 cells on osteoclastogenesis by inhibiting IFN-γ signaling in osteoclast precursor cells.
Grant S Schulert et al./2021 (145)	Bulk RNA-seq was performed on peripheral blood mononuclear cells and single cell (sc) RNA-seq analysis was performed on bone marrow macrophages from 26 Systemic juvenile idiopathic arthritis (SJIA) patients.	The positive regulator of IFN-γ signaling, TRIM8, was upregulated in SJIA patients. In addition, scRNA sequence analysis of BMM indicated that the IFN-γ response pathway was upregulated.
Edit Nagy et al./2017 (146)	Osteoclast precursor	Treatment of osteoclast precursors with IFN-γ decreased mRNA expression levels of TRAP, Cathepsin K, RANK, and TRAF6. Addition of neutralizing anti-IFN-γ antibody abolished these effects.
S Kamolmatyakul et al./2001 (147)	MOCP-5 and wild-type mouse bone marrow co-culture systems.	IFN-γ downregulated Cathepsin K mRNA expression in a time- and dose-dependent manner, and IFN-γ inhibited osteoclast formation only at early stages of osteoclast differentiation.
Haiyan Li et al./2014 (148)	Osteoclasts and T cells.	Activated T cells exert immunosuppressive functions by inducing IDO expression in OCs via IFN-γ.
Haruka Kohara et al./2011 (149)	Bone marrow macrophages.	IFN-γ indirectly regulates bone resorption and plays an osteoprotective role by inhibiting TNF-α stimulation-induced osteoclastogenesis and accelerating Fas/FasL signaling-mediated apoptosis.
Jingyi Tan et al./2021 (150)	Bone marrow macrophages.	IFN-γ significantly enhanced the upregulation of mRNA expression involving c-Fos, NFATc1, Ctsk, MMP-9, and TRAP in bone marrow macrophages, thereby promoting osteoclast differentiation.
Jiajia Xu et al./2016 (151)	Bone marrow mesenchymal stem cell	IL-12 and IL-23 indirectly inhibit BMMSC differentiation by increasing IFN-γ.
Zhongxiu Wang et al./2018 (152)	Primary osteoblasts	Higher ALP activity was observed in IL-17 and IFN-γ-treated primary osteoblasts.