Bone remodeling is a crucial physiological process for maintaining skeletal health. It focuses on the central roles of osteoblasts, osteoclasts, and osteocytes, as well as the composition of the bone's extracellular matrix. Furthermore, it explores the impact of hypoxia, or low oxygen levels, on bone health and elucidates the responsible molecular mechanisms. While bone remodeling units (BMUs), their cellular components, and the phases of the remodeling cycle remain not fully understood, the text also addresses systemic and local factors, including the critical RANK-RANKL-OPG pathway, that govern bone remodeling. This contributes to a comprehensive understanding of this intricate biological process.
Bone is a highly dynamic tissue that undergoes continuous remodeling to maintain skeletal health and strength. This remodeling process allows bones to adapt to various functional demands while serving essential functions such as supporting muscles, protecting vital organs, and storing calcium and phosphorus for metabolic processes [1]. The primary cellular components responsible for bone health are osteoblasts, osteoclasts, and osteocytes [1][2]. Bone's extracellular matrix comprises a mineral component, mainly hydroxyapatite, and an organic component, primarily collagen, along with non-collagenous proteins like sialoprotein, osteonectin, osteopontin, and osteocalcin. Mature bone can be classified into two histological types: cortical, which is dense and compact, accounting for 80% of total bone mass, and trabecular, which is lighter and less compact with an irregular structure [1][3].
Sufficient oxygen availability is of paramount importance to uphold the efficient functioning of cells and tissues. In instances where cells encounter an insufficiency of oxygen, termed hypoxia, they undergo intricate molecular and physiological adaptations to safeguard their viability[4]. Hypoxia can exert a significant impact on the intricate framework of bone health, disrupting the delicate equilibrium of bone remodeling processes [3].This interplay between oxygen levels and bone homeostasis underscores the intricate relationship between tissue oxygenation and skeletal integrity.
Bone remodeling is a precisely regulated process that occurs within specialized units known as bone remodeling units (BMUs). These BMUs comprise four principal cell types: bone lining cells, osteocytes, osteoclasts, and osteoblasts. Osteocytes, which are mature osteoblasts embedded within the bone matrix, play a pivotal role in detecting areas of skeletal weakness and orchestrating remodeling. Osteoclasts are responsible for bone resorption, while osteoblasts contribute to bone formation [5].
The bone remodeling cycle consists of several phases, including initiation, resorption, reversal, formation, and mineralization, each finely tuned by systemic factors such as parathyroid hormone and local regulators like growth factors and cytokines. Additionally, the RANK-RANKL-OPG pathway plays a crucial role in regulating bone remodeling [6][7].
Hypoxia on the other hand, is characterized by insufficient oxygen levels, can profoundly affect bone cell activity and remodeling. This review explores the impact of hypoxia on the main bone remodeling cells and their associated molecular pathways.
Osteocytes, derived from osteoblasts, are multifunctional cells embedded within the mineralized bone matrix. They play essential roles in regulating bone metabolism, acting as mechanosensors to detect and respond to mechanical stresses. Osteocytes produce sclerostin, a protein that inhibits bone formation by blocking the Wnt pathway. Additionally, osteocytes can stimulate bone resorption through RANKL secretion or inhibit it by producing OPG, which competes with RANKL [8][9].
Osteoclasts are specialized cells responsible for bone resorption. They differentiate from precursor cells and are regulated by various factors, including RANKL and macrophage colony-stimulating factor (M-CSF) [10]. Osteoclasts adhere to bone surfaces, create resorption gaps, and release hydrogen ions to acidify the environment, facilitating the degradation of bone matrix [11]. They also reabsorb detached materials, such as collagen and calcium. Osteoclast activation is a prerequisite for osteoblast activation, and this crosstalk is critical in bone remodeling [12].
Osteoblasts originate from mesenchymal progenitors and are involved in bone matrix formation and mineralization [13]. Transcription factors like Runx2, Sox9, and Atf-4 regulate osteoblast differentiation and maturation. Various growth factors, including TGF-β, IGF-1, and FGF, activate signaling pathways that influence osteoblast function. Osteoblasts are vital for bone formation and maintenance [12][14].
Hypoxia, characterized by low oxygen levels, triggers cellular responses mediated by hypoxia-inducible factors (HIFs). HIFs consist of oxygen-sensitive HIF-α subunits and constitutively expressed HIF-β subunits [15]. Under hypoxia, HIF-α accumulates and translocates to the nucleus, where it activates the expression of over 200 genes involved in survival mechanisms [16].
In bone tissue, which typically experiences oxygen levels around 6.6-8.5%, hypoxia can significantly impact bone cell function [17]. Hypoxia has been associated with reduced osteoblast differentiation and activity, delayed growth, and impaired matrix mineralization [18][19]. Conversely, it promotes osteoclastogenesis and enhances osteoclast resorptive capacity. These effects are mediated by various molecular pathways, including HIF-1α and HIF-2α [20].
Erythropoietin (EPO) is a hormone produced in response to hypoxia, stimulating red blood cell production [21]. EPO and its receptor (EPO-R) are also found in bone tissue, suggesting a potential role in bone metabolism [22]. EPO appears to have complex effects on bone, with some studies indicating that it stimulates osteogenesis through various signaling pathways, while others suggest it may lead to increased bone resorption [23][24]. EPO's influence on bone cells and its role in hypoxia-induced bone remodeling require further investigation [25].
Vitamin D is essential for calcium and phosphorus metabolism, cell proliferation, and immune system regulation [26]. The vitamin D receptor (VDR) mediates its effects when activated by calcitriol [26]. Hypoxia-induced inflammation, characterized by increased cytokine production, can activate NF-κB signaling [27]. Vitamin D has been shown to inhibit NF-κB pathway activation in immune cells and osteoclasts, suggesting a potential role in modulating the bone response to hypoxia [28].
Clinical studies investigating the effects of chronic hypoxia on bone metabolism in humans have yielded contradictory results [8][29][30]. Long-term exposure to sustained hypoxia has been associated with reduced bone health, while short exposures may not produce significant alterations [31]. Conditions like obstructive sleep apnea syndrome, characterized by intermittent hypoxia, have been linked to changes in bone remodeling markers, but the underlying mechanisms are complex and not fully understood.
Hypoxia-induced alterations in bone remodeling are a complex and multifaceted phenomenon involving intricate molecular pathways. Hypoxia influences the differentiation and activity of bone cells, with potential consequences for bone formation and resorption. The role of factors like EPO, vitamin D, and inflammation in modulating the bone response to hypoxia requires further investigation. Clinical studies on chronic hypoxia and bone health in humans present conflicting results, highlighting the need for more research in this area. Understanding the molecular mechanisms underlying hypoxia-induced bone remodeling is essential for developing strategies to mitigate its adverse effects on skeletal health.