Key Takeaways & Executive Findings
- •• Myeloid-derived suppressor cells (MDSCs) exhibit stronger osteoclast differentiation potential than bone marrow-derived macrophages in vitro. • In naturally aged mice, the proportion of MDSCs in bone marrow increases, and their osteoclastogenic ability is enhanced, correlating with bone loss. • In ovariectomy-induced osteoporosis, MDSC proportion and serum inflammatory cytokines (TNF-α, IL-6) are elevated, and MDSCs show enhanced osteoclast differentiation. • MDSCs may contribute to primary osteoporosis by promoting osteoclastogenesis under aging and estrogen deficiency conditions.
Abstract
BACKGROUND: Recent studies have found that immune cells play an important role in bone metabolism. Myeloid-derived suppressor cells, as a type of immunosuppressive cell, play a significant role in tumor development, but their role in primary osteoporosis remains unclear. OBJECTIVE: To investigate the osteoclastogenic potential of myeloid-derived suppressor cells in naturally aged and ovariectomy-induced osteoporosis mouse models. METHODS: (1) Myeloid-derived suppressor cells and bone marrow-derived macrophages were isolated from 6-8-week-old female C57BL/6 mice. Both cell types were induced for osteoclast differentiation. After 5 days of induction, osteoclast formation was detected by tartrate-resistant acid phosphatase staining. After 3 days of induction, mRNA expression of nuclear factor of activated T-cells 1 and osteoclast-associated immunoglobulin-like receptor was detected by qRT-PCR. (2) 6-8-week-old female C57BL/6 mice (young group, n=6) and 18-month-old female C57BL/6 mice (naturally aged group, n=6) were taken. Bone microstructure of the distal femur was analyzed by Micro-CT. Bone marrow cells were collected from both groups, and the proportion of myeloid-derived suppressor cells was detected by flow cytometry. Myeloid-derived suppressor cells were isolated and induced for osteoclast differentiation. After 5 days of induction, osteoclast formation was detected by tartrate-resistant acid phosphatase staining; after 3 days of induction, mRNA expression of nuclear factor of activated T-cells 1 and osteoclast-associated immunoglobulin-like receptor was detected by qRT-PCR. (3) 6-8-week-old female C57BL/6 mice were randomly divided into sham-operated group (n=6) and ovariectomy group (n=6). Eight weeks after ovariectomy, bone microstructure of the distal femur was analyzed by Micro-CT. Bone marrow cells were collected from both groups, and the proportion of myeloid-derived suppressor cells was detected by flow cytometry. Serum levels of tumor necrosis factor-alpha and interleukin-6 were measured by ELISA. Myeloid-derived suppressor cells were isolated and induced for osteoclast differentiation. After 5 days of induction, osteoclast formation was detected by tartrate-resistant acid phosphatase staining; after 3 days of induction, mRNA expression of nuclear factor of activated T-cells 1 and osteoclast-associated immunoglobulin-like receptor was detected by qRT-PCR. RESULTS AND CONCLUSION: (1) Tartrate-resistant acid phosphatase staining and qRT-PCR showed that the osteoclast differentiation ability of myeloid-derived suppressor cells was stronger than that of bone marrow-derived macrophages. (2) Micro-CT analysis showed that compared with the young group, the naturally aged group had lower bone mineral density, bone volume fraction, and trabecular number (P < 0.05), and increased trabecular separation (P < 0.05). The proportion of myeloid-derived suppressor cells in the naturally aged group was higher than that in the young group (P < 0.05). Tartrate-resistant acid phosphatase staining and qRT-PCR showed that the osteoclast differentiation ability of myeloid-derived suppressor cells in the naturally aged group was stronger than that in the young group. (3) Micro-CT analysis showed that compared with the sham-operated group, the ovariectomy group had lower bone mineral density, bone volume fraction, and trabecular number (P < 0.05), and increased trabecular separation (P < 0.05). The proportion of myeloid-derived suppressor cells and serum levels of tumor necrosis factor-alpha and interleukin-6 in the ovariectomy group were higher than those in the sham-operated group (P < 0.05). Tartrate-resistant acid phosphatase staining and qRT-PCR showed that the osteoclast differentiation ability of myeloid-derived suppressor cells in the ovariectomy group was stronger than that in the sham-operated group. (4) These results indicate that the proportion and osteoclastogenic ability of myeloid-derived suppressor cells increase under conditions of natural aging and estrogen deficiency, which may participate in the occurrence and development of osteoporosis.
1. Introduction
Osteoporosis is a common systemic skeletal disease characterized by decreased bone mass and deteriorated bone microarchitecture, leading to increased bone fragility and fracture risk [1]. With the aging of the population, the incidence of osteoporosis continues to rise, making it a major public health issue worldwide, often referred to as the 'silent epidemic of the 21st century' [2]. Based on etiology, osteoporosis can be classified into primary and secondary types. Primary osteoporosis includes idiopathic and degenerative types; idiopathic osteoporosis mainly occurs in children and young adults, and its pathogenesis remains unclear [3]; degenerative osteoporosis primarily affects middle-aged and elderly populations, and can be further divided into type I (postmenopausal) and type II (senile) based on clinical manifestations. The occurrence of osteoporosis is mainly attributed to the imbalance between osteoclastic bone resorption and osteoblastic bone formation during bone remodeling [4]. When osteoclast activity is enhanced or osteoblast function is impaired, bone resorption exceeds bone formation, ultimately leading to bone loss and structural damage, and thus the development of osteoporosis [5-6].
Bone marrow is an important source of immune cells, and its metabolic activity is closely related to immune responses [7]. In recent years, with the introduction of the concept of 'osteoimmunology', increasing research has focused on the interaction between bone and the immune system. Studies have found that bone cells can secrete various cytokines, chemokines, and growth factors, thereby affecting the development and function of immune cells [8-9]. Meanwhile, studies have shown that immune cells also play an important role in the development of osteoporosis. When immune cells are dysfunctional or overactivated, they may disrupt bone metabolic balance, leading to increased bone resorption and thus aggravating the progression of osteoporosis [10]. Among these, myeloid-derived suppressor cells (MDSCs), as a novel class of immunoregulatory cells, have gradually attracted attention. MDSCs are a group of immature immune cells derived from the myeloid lineage, possessing strong immunosuppressive functions. They are commonly expanded in pathological conditions such as cancer, inflammation, and infection, and have been shown to regulate immune responses. However, their role in bone metabolism, particularly in primary osteoporosis, remains largely unknown.
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CHENG Xin-yi, CHEN Yi-da, WANG Yi, LIU Dai-hui, ZHENG Yi, SHI Qin (2026). Role of myeloid-derived suppressor cells in osteoclast differentiation in primary osteoporosis. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21476
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Frequently Asked Questions
What are myeloid-derived suppressor cells (MDSCs)?
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that expand during pathological conditions such as cancer, inflammation, and infection. They possess strong immunosuppressive functions and can regulate immune responses. In the context of bone, MDSCs have been shown to have the potential to differentiate into osteoclasts, the bone-resorbing cells.
How does natural aging affect MDSCs and osteoporosis?
In naturally aged mice, the proportion of MDSCs in the bone marrow increases, and their osteoclastogenic ability is enhanced. This is associated with decreased bone mineral density, reduced bone volume fraction, and increased trabecular separation, indicating that aging-related changes in MDSCs may contribute to the development of osteoporosis.
What is the role of estrogen deficiency in MDSC-mediated osteoporosis?
Estrogen deficiency, as modeled by ovariectomy in mice, leads to an increase in the proportion of MDSCs in the bone marrow and elevated serum levels of inflammatory cytokines such as TNF-α and IL-6. These MDSCs exhibit enhanced osteoclast differentiation, which may exacerbate bone loss and contribute to postmenopausal osteoporosis.
What are the key findings of this study?
The study demonstrates that MDSCs have a stronger osteoclast differentiation potential compared to bone marrow-derived macrophages. In both naturally aged and ovariectomized mouse models of osteoporosis, the proportion of MDSCs increases, and their osteoclastogenic ability is enhanced, suggesting that MDSCs may play a role in the pathogenesis of primary osteoporosis.
What methods were used to assess osteoclast differentiation?
Osteoclast differentiation was assessed by tartrate-resistant acid phosphatase (TRAP) staining to detect osteoclast formation after 5 days of induction, and by quantitative real-time PCR (qRT-PCR) to measure mRNA expression of osteoclast-related genes, including nuclear factor of activated T-cells 1 (NFATc1) and osteoclast-associated immunoglobulin-like receptor (OSCAR), after 3 days of induction.
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