Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.
International journal of molecular sciences
Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.
10.3390/ijms251810116
Mitochondrial dysfunction in mammalian ageing.
Terzioglu Mügen,Larsson Nils-Göran
Novartis Foundation symposium
Ageing is likely a multifactorial process caused by accumulated damage to a variety of cellular components. Increasing age in mammals correlates with increased levels of mitochondrial DNA (mtDNA) mutations and deteriorating respiratory chain function. Mosaic respiratory chain deficiency in a subset of cells in various tissues, such as heart, skeletal muscle, colonic crypts and neurons, is typically found in aged humans. Experimental evidence in the mouse has linked increased levels of somatic mtDNA mutations to a variety of ageing phenotypes, such as osteoporosis, hair loss, greying of the hair, weight reduction and decreased fertility. It has been known for a long time that respiratory chain-deficient cells are more prone to undergo apoptosis and increased cell loss is therefore likely of importance in age-associated mitochondrial dysfunction. There is a tendency to automatically link mitochondrial dysfunction to increased production of reactive oxygen species (ROS). However, the experimental support for this concept is rather weak. Mouse models with respiratory chain deficiency induced by tissue-specific mtDNA depletion or by massive increase of point mutations in mtDNA have very minor or no increase of oxidative stress. Future studies are needed to address the relative importance of mitochondrial dysfunction and ROS in mammalian ageing.
10.1002/9780470725207.ch14
Cell life-or-death events in osteoporosis: All roads lead to mitochondrial dynamics.
Pharmacological research
Mitochondria exhibit heterogeneous shapes and networks within and among cell types and tissues, also in normal or osteoporotic bone tissues with complex cell types. This dynamic characteristic is determined by the high plasticity provided by mitochondrial dynamics and is stemmed from responding to the survival and functional requirements of various bone cells in a specific microenvironments. In contrast, mitochondrial dysfunction, induced by dysregulation of mitochondrial dynamics, may act as a trigger of cell death signals, including common apoptosis and other forms of programmed cell death (PCD). These PCD processes consisting of tightly structured cascade gene expression events, can further influence the bone remodeling by facilitating the death of various bone cells. Mitochondrial dynamics, therefore, drive the bone cells to stand at the crossroads of life and death by integrating external signals and altering metabolism, shape, and signal-response properties of mitochondria. This implies that targeting mitochondrial dynamics displays significant potential in treatment of osteoporosis. Considerable effort has been made in osteoporosis to emphasize the parallel roles of mitochondria in regulating energy metabolism, calcium signal transduction, oxidative stress, inflammation, and cell death. However, the emerging field of mitochondrial dynamics-related PCD is not well understood. Herein, to bridge the gap, we outline the latest knowledge on mitochondrial dynamics regulating bone cell life or death during normal bone remodeling and osteoporosis.
10.1016/j.phrs.2024.107383
Autophagy in Bone Remodeling: A Regulator of Oxidative Stress.
Frontiers in endocrinology
Bone homeostasis involves bone formation and bone resorption, which are processes that maintain skeletal health. Oxidative stress is an independent risk factor, causing the dysfunction of bone homeostasis including osteoblast-induced osteogenesis and osteoclast-induced osteoclastogenesis, thereby leading to bone-related diseases, especially osteoporosis. Autophagy is the main cellular stress response system for the limination of damaged organelles and proteins, and it plays a critical role in the differentiation, apoptosis, and survival of bone cells, including bone marrow stem cells (BMSCs), osteoblasts, osteoclasts, and osteocytes. High evels of reactive oxygen species (ROS) induced by oxidative stress induce autophagy to protect against cell damage or even apoptosis. Additionally, pathways such as ROS/FOXO3, ROS/AMPK, ROS/Akt/mTOR, and ROS/JNK/c-Jun are involved in the regulation of oxidative stress-induced autophagy in bone cells, including osteoblasts, osteocytes and osteoclasts. This review discusses how autophagy regulates bone formation and bone resorption following oxidative stress and summarizes the potential protective mechanisms exerted by autophagy, thereby providing new insights regarding bone remodeling and potential therapeutic targets for osteoporosis.
10.3389/fendo.2022.898634
Oxidative stress: A common pathological state in a high-risk population for osteoporosis.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Osteoporosis is becoming a major concern in the field of public health. The process of bone loss is insidious and does not directly induce obvious symptoms. Complications indicate an irreversible decrease in bone mass. The high-risk populations of osteoporosis, including postmenopausal women, elderly men, diabetic patients and obese individuals need regular bone mineral density testing and appropriate preventive treatment. However, the primary changes in these populations are different, increasing the difficulty of effective treatment of osteoporosis. Determining the core pathogenesis of osteoporosis helps improve the efficiency and efficacy of treatment among these populations. Oxidative stress is a common pathological state secondary to estrogen deficiency, aging, hyperglycemia and hyperlipemia. In this review, we divided oxidative stress into the direct effect of reactive oxygen species (ROS) and the reduction of antioxidant enzyme activity to discuss their roles in the development of osteoporosis. ROS initiated mitochondrial apoptotic signaling and suppressed osteogenic marker expression to weaken osteogenesis. MAPK and NF-κB signaling pathways mediated the positive effect of ROS on osteoclast differentiation. Antioxidant enzymes not only eliminate the negative effects of ROS, but also directly participate in the regulation of bone metabolism. Additionally, we also described the roles of proinflammatory factors and HIF-1α under the pathophysiological changes of inflammation and hypoxia, which provided a supplement of oxidative stress-induced osteoporosis. In conclusion, our review showed that oxidative stress was a common pathological state in a high-risk population for osteoporosis. Targeted oxidative stress treatment would greatly optimize the therapeutic schedule of various osteoporosis treatments.
10.1016/j.biopha.2023.114834
Skeletal Aging and Osteoporosis: Mechanisms and Therapeutics.
Chandra Abhishek,Rajawat Jyotika
International journal of molecular sciences
Bone is a dynamic organ maintained by tightly regulated mechanisms. With old age, bone homeostasis, which is maintained by an intricate balance between bone formation and bone resorption, undergoes deregulation. Oxidative stress-induced DNA damage, cellular apoptosis, and cellular senescence are all responsible for this tissue dysfunction and the imbalance in the bone homeostasis. These cellular mechanisms have become a target for therapeutics to treat age-related osteoporosis. Genetic mouse models have shown the importance of senescent cell clearance in alleviating age-related osteoporosis. Furthermore, we and others have shown that targeting cellular senescence pharmacologically was an effective tool to alleviate age- and radiation-induced osteoporosis. Senescent cells also have an altered secretome known as the senescence associated secretory phenotype (SASP), which may have autocrine, paracrine, or endocrine function. The current review discusses the current and potential pathways which lead to a senescence profile in an aged skeleton and how bone homeostasis is affected during age-related osteoporosis. The review has also discussed existing therapeutics for the treatment of osteoporosis and rationalizes for novel therapeutic options based on cellular senescence and the SASP as an underlying pathogenesis of an aging bone.
10.3390/ijms22073553
Ferroptosis: Regulatory mechanisms and potential targets for bone metabolism: A review.
Medicine
Bone homeostasis is a homeostasis process constructed by osteoblast bone formation and osteoclast bone resorption. Bone homeostasis imbalance and dysfunction are the basis for the development of various orthopedic diseases such as osteoporosis, osteoarthritis, and steroid-induced avascular necrosis of femoral head. Previous studies have demonstrated that ferroptosis can induce lipid peroxidation through the generation of reactive oxygen species, activate a number of signaling pathways, and participate in the regulation of osteoblast bone formation and osteoclast bone resorption, resulting in bone homeostasis imbalance, which is an important factor in the pathogenesis of many orthopedic diseases, but the mechanism of ferroptosis is still unknown. In recent years, it has been found that, in addition to iron metabolism and intracellular antioxidant system imbalance, organelle dysfunction is also a key factor affecting ferroptosis. This paper takes this as the starting point, reviews the latest literature reports at home and abroad, elaborates the pathogenesis and regulatory pathways of ferroptosis and the relationship between ferroptosis and various organelles, and summarizes the mechanism by which ferroptosis mediates bone homeostasis imbalance, with the aim of providing new directions for the research related to ferroptosis and new ideas for the prevention and treatment of bone and joint diseases.
10.1097/MD.0000000000039158
An update on the role of ferroptosis in the pathogenesis of osteoporosis.
EFORT open reviews
Ferroptosis is a novel form of programmed cell death, distinguished from apoptosis, autophagy, and programmed necrosis and has received much attention since it was defined in 2012. Ferroptotic cells physiologically exhibit iron metabolism dysregulation, oxidative stress, and lipid peroxidation. Morphologically, they show plasma membrane disruption, cytoplasmic swelling, and mitochondrial condensation. Osteoporosis is taken more and more seriously as the proportion of the aging population continues to increase globally. Interestingly, ferroptosis has been demonstrated to be involved in the development and progression of osteoporosis in many extant studies. The review summarizes iron metabolism, lipid peroxidation, and the different regulatory signals in ferroptosis. Changes in signaling mechanisms within osteoblasts, osteoclasts, and osteocytes after ferroptosis occur are explained here. Studies showed ferroptosis play an important role in different osteoporosis models (diabetes osteoporosis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis). Inhibitors and EC (Exos) targeting ferroptosis could ameliorate bone loss in osteoporotic mice by protecting cells against lipid peroxidation. Shortly, we hope that more effective and appropriate clinical therapy means will be utilized in the treatment of osteoporosis.
10.1530/EOR-23-0148
Ferroptosis: A New Regulatory Mechanism in Osteoporosis.
Liu Pan,Wang Wenzhao,Li Zheng,Li Yao,Yu Xiaoping,Tu Ji,Zhang Zhengdong
Oxidative medicine and cellular longevity
Osteoporosis can be caused by a multitude of factors and is defined by a decrease in bone density and mass caused by the destruction of bone microstructure, resulting in increased bone brittleness. Thus, it is a systemic bone disease in which patients are prone to fracture. The role of ferroptosis in the pathogenesis of osteoporosis has become a topic of growing interest. In this review, we discuss the cell morphology, basic mechanisms of ferroptosis, the relationship between ferroptosis and osteoclasts and osteoblasts, as well as the relationship between ferroptosis and diabetic osteoporosis, steroid-induced osteoporosis, and postmenopausal osteoporosis. Emerging biomedical research has provided new insights into the roles of ferroptosis and osteoporosis, such as in cellular function, signaling pathways, drug inhibition, and gene silencing. The pathophysiology and mechanism of ferroptosis and osteoporosis need to be further studied and elucidated to broaden our understanding of iron metabolism and immune regulation. Studies using animal models of osteoporosis in vivo and cell models in vitro will help clarify the relationship between ferroptosis and osteoporosis and provide research ideas for the elucidation of new mechanisms and development of new technologies and new drugs for the treatment of osteoporosis in the future.
10.1155/2022/2634431
Ferroptosis and musculoskeletal diseases: "Iron Maiden" cell death may be a promising therapeutic target.
Frontiers in immunology
Ferroptosis is a novel form of cell death precisely regulated by iron metabolism, antioxidant processes, and lipid metabolism that plays an irreplaceable role in the development of many diseases. Musculoskeletal disorders (MSKs), including osteoporosis, osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, sarcopenia, and rhabdomyolysis, have become one of the most common causes of disability and a major burden on public health and social care systems. The mechanism of ferroptosis in MSKs has recently been elucidated. In this review, we briefly introduce the ferroptosis mechanism and illustrate the pathological roles of ferroptosis in MSKs with a focus on how ferroptosis can be exploited as a promising treatment strategy. Notably, because the toxicity of compounds that inhibit or induce ferroptosis in other organs is largely unknown, ferroptosis appears to be a double-edged sword. We point out that more research is needed in the future to verify the therapeutic effects based on ferroptosis in MSKs.
10.3389/fimmu.2022.972753