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Background <p>The disruption of bone immune function and bone metabolism homeostasis is intricately linked to the onset and progression of glucocorticoid-induced osteoporosis (GIOP). From the perspective of indirect pharmacology, bone immune cells act as critical intermediate mediators that bridge systemic drug exposure and local bone tissue responses. Wubi Shanyao Pills (WBSY), a Chinese patent medicine, have been shown to modulate T lymphocyte levels in naturally aging mice and improve bone strength. However, whether WBSY exerts anti-GIOP effects through an indirect immunomodulatory pattern and its underlying intermediate mechanisms remain unclear.</p> Purpose <p>This study aims to elucidate the effects and mechanisms of WBSY on GIOP in mice.</p> Methods <p>Initially, the chemical constituents of WBSY were characterized using high-performance liquid chromatography (HPLC). Following this, a GIOP mouse model was developed through intraperitoneal administration of dexamethasone at a dosage of 10&#xa0;mg/kg every three days. The mice were subsequently treated with WBSY at varying dosages—high (1.5&#xa0;g/kg), medium (0.75&#xa0;g/kg), and low (0.375&#xa0;g/kg)—via gavage over a 20-week duration. Throughout the experimental period, general physiological parameters of the mice were systematically monitored. Bone mass alterations were subsequently assessed through bone strength measurements, micro-computed tomography analysis of bone tissue, and histopathological examination. Potential target pathways were identified via transcriptomic analysis. Furthermore, bone immunology-related parameters were evaluated using flow cytometry, including the proportion of T lymphocytes in the spleen and bone marrow, as well as the expression levels of the CXC chemokine ligand 10-chemokine receptor 3 (CXCL10-CXCR3) axis. Concurrently, key indicators of the bone metabolism pathway, such as the Receptor Activator of Nuclear Factor-κB (RANK), Receptor Activator of Nuclear Factor-κB ligand (RANKL), and osteoprotegerin (OPG), were further analyzed.</p> Results <p>The results of the HPLC analysis demonstrated that the concentrations of echinacoside, acteoside, and schisandrol in WBSY were 7.82&#xa0;mg/g, 2.18&#xa0;mg/g, and 0.32&#xa0;mg/g, respectively. Subsequently, the findings revealed that WBSY significantly enhanced general physiological parameters, including body weight, grip strength, and anal/back temperature, in GIOP mice. WBSY not only enhanced bone strength and mitigated pathological damage to the femur, but also significantly improved bone microarchitecture. This improvement was evidenced by an increase in bone volume/tissue volume, trabecular thickness, and trabecular number, alongside a reduction in trabecular separation and the structural model index. Furthermore, transcriptomic analysis indicated that WBSY may exert anti-GIOP effects by modulating key pathways, including osteoclast differentiation, interleukin-17A (IL-17A), and nuclear factor kappa B (NF-κB). At the immunological level, WBSY was shown to increase the proportion of T cells, B cells, and CD4⁺ T cells in the spleen, downregulate the expression of CXCL10 and CXCR3, and inhibit the activation of CD4⁺ Th17 cells in the femur. At the molecular level, WBSY modulated the expression of key molecules involved in the bone metabolism pathway, including RANK, RANKL, and OPG. It consistently downregulated the levels of femoral inflammation signaling molecules such as tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylated IκB kinase β/IκB kinase β (p-IKKβ/IKKβ), and phosphorylated nuclear factor kappa B/nuclear factor kappa B (p-NF-κB/NF-κB). Additionally, WBSY reduced the concentrations of bone resorption markers, including tartrate-resistant acid phosphatase (TRAP) and β-C-telopeptide of type I collagen (β-CTX). Concurrently, it upregulated the expression of osteogenic molecules such as Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP2), leading to increased concentrations of bone formation markers, including bone-specific alkaline phosphatase (BALP), procollagen type I N-terminal propeptide (PINP), and osteocalcin (BGP).</p> Conclusions <p>In summary, this study suggests that WBSY exerts anti-GIOP effects via an indirect pharmacological mechanism. WBSY may modulate the CXCL10-CXCR3 axis to inhibit aberrant T cell homing to the bone marrow, thereby reducing the excessive activation of bone marrow-resident Th17 cells and the secretion of the key bridging cytokine IL-17A. This indirect immunomodulation may subsequently restore the balance of the RANKL/RANK/OPG pathway, ultimately synergistically promoting bone formation and inhibiting bone resorption.</p> Graphical Abstract <p></p>

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Wubi Shanyao Pills ameliorate glucocorticoid-induced osteoporosis by regulating bone marrow T cell homing as an immune intermediate to restore bone metabolism

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  • 发表日期：

    2026年7月2日

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  • Ying-Jie Dong,
  • Jia-Yue Zhu,
  • Jie Su,
  • Ya-Wen Sun,
  • Er-Xiao Chen,
  • Xiao-Hu Jin,
  • Gui-Yuan Lv,
  • Su-Hong Chen

摘要

Background

The disruption of bone immune function and bone metabolism homeostasis is intricately linked to the onset and progression of glucocorticoid-induced osteoporosis (GIOP). From the perspective of indirect pharmacology, bone immune cells act as critical intermediate mediators that bridge systemic drug exposure and local bone tissue responses. Wubi Shanyao Pills (WBSY), a Chinese patent medicine, have been shown to modulate T lymphocyte levels in naturally aging mice and improve bone strength. However, whether WBSY exerts anti-GIOP effects through an indirect immunomodulatory pattern and its underlying intermediate mechanisms remain unclear.

Purpose

This study aims to elucidate the effects and mechanisms of WBSY on GIOP in mice.

Methods

Initially, the chemical constituents of WBSY were characterized using high-performance liquid chromatography (HPLC). Following this, a GIOP mouse model was developed through intraperitoneal administration of dexamethasone at a dosage of 10 mg/kg every three days. The mice were subsequently treated with WBSY at varying dosages—high (1.5 g/kg), medium (0.75 g/kg), and low (0.375 g/kg)—via gavage over a 20-week duration. Throughout the experimental period, general physiological parameters of the mice were systematically monitored. Bone mass alterations were subsequently assessed through bone strength measurements, micro-computed tomography analysis of bone tissue, and histopathological examination. Potential target pathways were identified via transcriptomic analysis. Furthermore, bone immunology-related parameters were evaluated using flow cytometry, including the proportion of T lymphocytes in the spleen and bone marrow, as well as the expression levels of the CXC chemokine ligand 10-chemokine receptor 3 (CXCL10-CXCR3) axis. Concurrently, key indicators of the bone metabolism pathway, such as the Receptor Activator of Nuclear Factor-κB (RANK), Receptor Activator of Nuclear Factor-κB ligand (RANKL), and osteoprotegerin (OPG), were further analyzed.

Results

The results of the HPLC analysis demonstrated that the concentrations of echinacoside, acteoside, and schisandrol in WBSY were 7.82 mg/g, 2.18 mg/g, and 0.32 mg/g, respectively. Subsequently, the findings revealed that WBSY significantly enhanced general physiological parameters, including body weight, grip strength, and anal/back temperature, in GIOP mice. WBSY not only enhanced bone strength and mitigated pathological damage to the femur, but also significantly improved bone microarchitecture. This improvement was evidenced by an increase in bone volume/tissue volume, trabecular thickness, and trabecular number, alongside a reduction in trabecular separation and the structural model index. Furthermore, transcriptomic analysis indicated that WBSY may exert anti-GIOP effects by modulating key pathways, including osteoclast differentiation, interleukin-17A (IL-17A), and nuclear factor kappa B (NF-κB). At the immunological level, WBSY was shown to increase the proportion of T cells, B cells, and CD4⁺ T cells in the spleen, downregulate the expression of CXCL10 and CXCR3, and inhibit the activation of CD4⁺ Th17 cells in the femur. At the molecular level, WBSY modulated the expression of key molecules involved in the bone metabolism pathway, including RANK, RANKL, and OPG. It consistently downregulated the levels of femoral inflammation signaling molecules such as tumor necrosis factor receptor-associated factor 6 (TRAF6), phosphorylated IκB kinase β/IκB kinase β (p-IKKβ/IKKβ), and phosphorylated nuclear factor kappa B/nuclear factor kappa B (p-NF-κB/NF-κB). Additionally, WBSY reduced the concentrations of bone resorption markers, including tartrate-resistant acid phosphatase (TRAP) and β-C-telopeptide of type I collagen (β-CTX). Concurrently, it upregulated the expression of osteogenic molecules such as Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP2), leading to increased concentrations of bone formation markers, including bone-specific alkaline phosphatase (BALP), procollagen type I N-terminal propeptide (PINP), and osteocalcin (BGP).

Conclusions

In summary, this study suggests that WBSY exerts anti-GIOP effects via an indirect pharmacological mechanism. WBSY may modulate the CXCL10-CXCR3 axis to inhibit aberrant T cell homing to the bone marrow, thereby reducing the excessive activation of bone marrow-resident Th17 cells and the secretion of the key bridging cytokine IL-17A. This indirect immunomodulation may subsequently restore the balance of the RANKL/RANK/OPG pathway, ultimately synergistically promoting bone formation and inhibiting bone resorption.

Graphical Abstract