Key Takeaways & Executive Findings
- •• The bone-blood axis represents a bidirectional regulatory network between skeletal and hematopoietic systems, crucial for maintaining bone mass and hematopoietic function. • Core signaling pathways (Wnt/β-catenin, Notch, RANK/RANKL/OPG, Hippo-YAP) mediate the crosstalk, with immune cells acting as key bridges. • Metabolic products like lactate and 2-hydroxyglutarate serve as intercellular signaling molecules linking metabolism and epigenetics in bone remodeling and hematopoietic fate. • Targeting the bone-blood axis (e.g., with denosumab or enasidenib) offers promising therapeutic strategies for cross-system diseases such as osteoporosis and leukemia.
Abstract
BACKGROUND: The bone marrow serves not only as a primary hematopoietic organ but also as an essential component of bone tissue. The bone marrow microenvironment is a critical niche for maintaining hematopoietic stem cell function, while the hematopoietic process itself can regulate bone remodeling and maintain bone mass stability. The precise synergistic interaction between the skeletal and hematopoietic systems maintains the health of both blood and bone, yet a systematic summary of these interactions is lacking. OBJECTIVE: To systematically review the research progress on the interactions between the skeletal and hematopoietic systems, aiming to provide a reference for their mutual regulation and to explore potential therapeutic targets for blood diseases such as anemia and leukemia, and bone diseases such as osteoporosis and osteoarthritis. METHODS: A search of CNKI, Wanfang, and PubMed databases was conducted for literature published from January 2000 to July 2025 using keywords including 'bone mass regulation', 'hematopoietic function', 'bone marrow microenvironment', and 'bone and blood axis'. A total of 115 articles were included for analysis. RESULTS AND CONCLUSION: (1) The bidirectional regulatory network of the 'bone-blood axis' in the bone marrow microenvironment and its core mechanisms were systematically elaborated. (2) The bone marrow microenvironment, as a dynamic system composed of multiple cellular and non-cellular components, precisely regulates the quiescence, self-renewal, and differentiation of hematopoietic stem cells through core signaling pathways such as Wnt/β-catenin, Notch, RANK/RANKL/OPG, and Hippo-YAP, while also receiving reverse regulation from the hematopoietic system. (3) This bidirectional dialogue also dominates bone remodeling, with immune cells (e.g., macrophages and T lymphocytes) serving as key bridges connecting the skeletal and hematopoietic systems by secreting specific factors. (4) Imbalance in this dialogue network is an important pathological basis for the occurrence of cross-system diseases such as osteoporosis, myelofibrosis, and leukemia. (5) This article provides a new perspective for understanding the bone marrow microenvironment through the framework of the 'bone-blood axis', revealing the co-pathogenesis of blood and bone diseases. Targeting key signaling nodes of this axis or utilizing synergistic intervention strategies (e.g., denosumab, enasidenib) may open new avenues for integrated treatment of cross-system diseases in the future.
1. Introduction
The skeletal system, besides being a crucial component of the locomotor system, also serves as the supporting structure for the bone marrow. The spatial proximity of bone and bone marrow provides a physiological basis for their functional interconnection. In 1978, Schofield et al. first proposed the concept of the 'bone marrow niche', emphasizing that the microenvironment composed of stromal cells is essential for the survival of hematopoietic stem cells (HSCs). Subsequent studies have further demonstrated that this 'bone marrow niche', composed of bone marrow stromal cells, immune cells, and cytokines, provides structural support for HSCs and precisely regulates their self-renewal, proliferation, differentiation, and metabolism, playing a vital role in maintaining HSC quiescence, stemness, and hematopoietic lineage commitment [1-2].
In recent years, with the discovery of the endocrine effects of bone tissue, the 'bone marrow niche' has been increasingly recognized not only for providing structural support but also for regulating HSC behavior through the secretion of cytokines and other factors [3], making it a new hotspot of research. Beyond the regulation of hematopoiesis by the bone marrow microenvironment, HSCs can also reversely regulate the bone marrow microenvironment, thereby creating a suitable 'soil' for themselves. As the most important mechanical/chemical component of the bone marrow microenvironment, bone tissue undergoes numerous changes under the regulation of HSCs, manifesting as pathophysiological alterations in the skeletal system and regulatory effects on HSCs. The authors refer to this bidirectional regulatory network between bone and the hematopoietic system as the 'bone-blood axis'. The dysregulation of this homeostasis holds significant research value in the pathogenesis of skeletal and hematological diseases.
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Hong Linling, Zhang Kunpeng, Zheng Liming, Ye Baodong, Liu Jingjing (2026). Role of bone–blood axis in bone mass regulation and hematopoietic function maintenance. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21540
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Frequently Asked Questions
What is the bone-blood axis?
The bone-blood axis refers to the bidirectional regulatory network between the skeletal and hematopoietic systems, involving direct cell-cell contact, paracrine signaling, and metabolic exchange between bone cells (e.g., osteoblasts, osteoclasts, osteocytes) and blood cells (e.g., hematopoietic stem cells, myeloid and lymphoid cells).
How does the bone marrow microenvironment regulate hematopoiesis?
The bone marrow microenvironment regulates hematopoiesis through core signaling pathways such as Wnt/β-catenin, Notch, RANK/RANKL/OPG, and Hippo-YAP, which control HSC quiescence, self-renewal, and differentiation. Additionally, metabolic products like lactate and 2-hydroxyglutarate act as signaling molecules influencing hematopoietic fate.
What are the clinical implications of the bone-blood axis?
Dysregulation of the bone-blood axis is implicated in diseases such as osteoporosis, myelofibrosis, and leukemia. Targeting key signaling nodes or using synergistic interventions (e.g., denosumab, enasidenib) may offer novel therapeutic strategies for these cross-system diseases.
What are the key signaling pathways in the bone-blood axis?
Key signaling pathways include Wnt/β-catenin, Notch, RANK/RANKL/OPG, and Hippo-YAP. These pathways mediate the crosstalk between bone cells and hematopoietic cells, regulating both bone remodeling and hematopoiesis.
What is the role of immune cells in the bone-blood axis?
Immune cells such as macrophages and T lymphocytes act as bridges between the skeletal and hematopoietic systems by secreting specific factors that influence both bone remodeling and hematopoietic regulation.
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