Association of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease and retinopathy in type 2 diabetes.

BACKGROUND: Novel biomarkers of vascular disease in diabetes could help identify new mechanistic pathways. Osteocalcin, osteoprotegerin, and osteopontin are key molecules involved in bone and vascular calcification processes, both of which are compromised in diabetes. We aimed to evaluate possible associations of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease (CVD) and diabetic retinopathy (DR) among people with type 2 diabetes (T2D). MATERIALS AND METHODS: Osteocalcin, osteoprotegerin, and osteopontin concentrations were measured at enrolment in 848 participants with T2D from the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study (ClinicalTrials.gov: NCT02311244). Logistic regression models and propensity score matching were used to assess possible associations of osteocalcin, osteoprotegerin, and osteopontin with a history of CVD and with evidence of any grade of DR adjusting for confounders. RESULTS: Previous CVD was reported in 139 (16.4%) participants, while 144 (17.0%) had DR. After adjusting for possible confounders, osteocalcin but not osteoprotegerin or osteopontin concentrations were associated with a history of CVD (Odds Ratio [OR] and 95% CI for one standard deviation (SD) increase in osteocalcin concentrations (natural log): 1.35 (1.06-1.72), p = 0.014). Associations with prevalent DR were seen for osteoprotegerin (OR for one SD increase in osteoprotegerin concentrations (natural log): 1.25 (1.01-1.55), p = 0.047) and osteopontin (OR for one SD increase in osteopontin concentrations (natural log): 1.25 (1.02-1.53), p = 0.022), but not osteocalcin. CONCLUSIONS: In T2D, higher serum osteocalcin concentrations are associated with macrovascular complications and higher osteoprotegerin and osteopontin concentrations with microvascular complications, suggesting that these osteokines might be involved in pathways directly related to vascular disease.

Metabolic Health and Disease: A Role of Osteokines?

Maintenance of skeletal health is tightly regulated by osteocytes, osteoblasts, and osteoclasts via coordinated secretion of bone-derived factors, termed osteokines. Disruption of this coordinated process due to aging and metabolic disease promotes loss of bone mass and increased risk of fracture. Indeed, growing evidence demonstrates that metabolic diseases, including type 2 diabetes, liver disease and cancer are accompanied by bone loss and altered osteokine levels. With the persistent prevalence of cancer and the growing epidemic of metabolic disorders, investigations into the role of inter-tissue communication during disease progression are on the rise. While osteokines are imperative for bone homeostasis, work from us and others have identified that osteokines possess endocrine functions, exerting effects on distant tissues including skeletal muscle and liver. In this review we first discuss the prevalence of bone loss and osteokine alterations in patients with type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cirrhosis, and cancer. We then discuss the effects of osteokines in mediating skeletal muscle and liver homeostasis, including RANKL, sclerostin, osteocalcin, FGF23, PGE2, TGF-ß, BMPs, IGF-1 and PTHrP. To better understand how inter-tissue communication contributes to disease progression, it is essential that we include the bone secretome and the systemic roles of osteokines.

Organokines in Rheumatoid Arthritis: A Critical Review.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that primarily affects the joints. Organokines can produce beneficial or harmful effects in this condition. Among RA patients, organokines have been associated with increased inflammation and cartilage degradation due to augmented cytokines and metalloproteinases production, respectively. This study aimed to perform a review to investigate the role of adipokines, osteokines, myokines, and hepatokines on RA progression. PubMed, Embase, Google Scholar, and Cochrane were searched, and 18 studies were selected, comprising more than 17,000 RA patients. Changes in the pattern of organokines secretion were identified, and these could directly or indirectly contribute to aggravating RA, promoting articular alterations, and predicting the disease activity. In addition, organokines have been implicated in higher radiographic damage, immune dysregulation, and angiogenesis. These can also act as RA potent regulators of cells proliferation, differentiation, and apoptosis, controlling osteoclasts, chondrocytes, and fibroblasts as well as immune cells chemotaxis to RA sites. Although much is already known, much more is still unknown, principally about the roles of organokines in the occurrence of RA extra-articular manifestations.

Organokines, Sarcopenia, and Metabolic Repercussions: The Vicious Cycle and the Interplay with Exercise.

Sarcopenia is a disease that becomes more prevalent as the population ages, since it is directly linked to the process of senility, which courses with muscle atrophy and loss of muscle strength. Over time, sarcopenia is linked to obesity, being known as sarcopenic obesity, and leads to other metabolic changes. At the molecular level, organokines act on different tissues and can improve or harm sarcopenia. It all depends on their production process, which is associated with factors such as physical exercise, the aging process, and metabolic diseases. Because of the seriousness of these repercussions, the aim of this literature review is to conduct a review on the relationship between organokines, sarcopenia, diabetes, and other metabolic repercussions, as well the role of physical exercise. To build this review, PubMed-Medline, Embase, and COCHRANE databases were searched, and only studies written in English were included. It was observed that myokines, adipokines, hepatokines, and osteokines had direct impacts on the pathophysiology of sarcopenia and its metabolic repercussions. Therefore, knowing how organokines act is very important to know their impacts on age, disease prevention, and how they can be related to the prevention of muscle loss.

Homo sapiens May Incorporate Daily Acute Cycles of "Conditioning-Deconditioning" to Maintain Musculoskeletal Integrity: Need to Integrate with Biological Clocks and Circadian Rhythm Mediators.

Human evolution required adaptation to the boundary conditions of Earth, including 1 g gravity. The bipedal mobility of Homo sapiens in that gravitational field causes ground reaction force (GRF) loading of their lower extremities, influencing the integrity of the tissues of those extremities. However, humans usually experience such loading during the day and then a period of relative unloading at night. Many studies have indicated that loading of tissues and cells of the musculoskeletal (MSK) system can inhibit their responses to biological mediators such as cytokines and growth factors. Such findings raise the possibility that humans use such cycles of acute conditioning and deconditioning of the cells and tissues of the MSK system to elaborate critical mediators and responsiveness in parallel with these cycles, particularly involving GRF loading. However, humans also experience circadian rhythms with the levels of a number of mediators influenced by day/night cycles, as well as various levels of biological clocks. Thus, if responsiveness to MSK-generated mediators also occurs during the unloaded part of the daily cycle, that response must be integrated with circadian variations as well. Furthermore, it is also possible that responsiveness to circadian rhythm mediators may be regulated by MSK tissue loading. This review will examine evidence for the above scenario and postulate how interactions could be both regulated and studied, and how extension of the acute cycles biased towards deconditioning could lead to loss of tissue integrity.

Muscle-Bone Crosstalk in Chronic Kidney Disease: The Potential Modulatory Effects of Exercise.

Chronic kidney disease (CKD) is a prevalent worldwide public burden that increasingly compromises overall health as the disease progresses. Two of the most negatively affected tissues are bone and skeletal muscle, with CKD negatively impacting their structure, function and activity, impairing the quality of life of these patients and contributing to morbidity and mortality. Whereas skeletal health in this population has conventionally been associated with bone and mineral disorders, sarcopenia has been observed to impact skeletal muscle health in CKD. Indeed, bone and muscle tissues are linked anatomically and physiologically, and together regulate functional and metabolic mechanisms. With the initial crosstalk between the skeleton and muscle proposed to explain bone formation through muscle contraction, it is now understood that this communication occurs through the interaction of myokines and osteokines, with the skeletal muscle secretome playing a pivotal role in the regulation of bone activity. Regular exercise has been reported to be beneficial to overall health. Also, the positive regulatory effect that exercise has been proposed to have on bone and muscle anatomical, functional, and metabolic activity has led to the proposal of regular physical exercise as a therapeutic strategy for muscle and bone-related disorders. The detection of bone- and muscle-derived cytokine secretion following physical exercise has strengthened the idea of a cross communication between these organs. Hence, this review presents an overview of the impact of CKD in bone and skeletal muscle, and narrates how these tissues intrinsically communicate with each other, with focus on the potential effect of exercise in the modulation of this intercommunication.

Muscle-bone axis in children with chronic kidney disease: current knowledge and future perspectives.

Bone and muscle tissue are developed hand-in-hand during childhood and adolescence and interact through mechanical loads and biochemical pathways forming the musculoskeletal system. Chronic kidney disease (CKD) is widely considered as both a bone and muscle-weakening disease, eventually leading to frailty phenotype, with detrimental effects on overall morbidity. CKD also interferes in the biomechanical communication between two tissues. Pathogenetic mechanisms including systemic inflammation, anorexia, physical inactivity, vitamin D deficiency and secondary hyperparathyroidism, metabolic acidosis, impaired growth hormone/insulin growth factor 1 axis, insulin resistance, and activation of renin-angiotensin system are incriminated for longitudinal uncoordinated loss of bone mineral content, bone strength, muscle mass, and muscle strength, leading to mechanical impairment of the functional muscle-bone unit. At the same time, CKD may also interfere in the biochemical crosstalk between the two organs, through inhibiting or stimulating the expression of certain osteokines and myokines. This review focuses on presenting current knowledge, according to in vitro, in vivo, and clinical studies, concerning the pathogenetic pathways involved in the muscle-bone axis, and suggests approaches aimed at preventing bone loss and muscle wasting in the pediatric population. Novel therapeutic targets for preserving musculoskeletal health in the context of CKD are also discussed.

Muscle, Bone, and Fat Crosstalk: the Biological Role of Myokines, Osteokines, and Adipokines.

PURPOSE OF REVIEW: Skeletal muscle and bone are connected anatomically and physiologically, and play a crucial role in human locomotion and metabolism. Historically, the coupling between muscle and bone has been viewed in light of mechanotransduction, which dictates that the mechanical forces applied to muscle are transmitted to the skeleton to initiate bone formation. However, these organs also communicate through the endocrine system, orchestrated by a family of cytokines namely myokines (derived from myocytes) and osteokines (derived from bone cells). A third player in this biochemical crosstalk is adipose tissue and the secretion of adipokines (derived from adipocytes). In this review, we discuss the bidirectional effects of myokines and osteokines on muscle and bone metabolism, and the impact of adipokines on both of these secretory organs. RECENT FINDINGS: Several myokines, notably, IL6, irisin, IGF-1, BDNF, myostatin, and FGF2 exert anabolic/catabolic effects on bone, while the osteokines osteocalcin and sclerostin have shown to induce muscle anabolism and catabolism, respectively. Adipokines, such as leptin, resistin, adiponectin, and TNFα (released from adipose tissue), can also modulate muscle and bone metabolism. Contrarily, exercise-mediated release of lipolytic myokines (IL6, irisin, and LIF) stimulates thermogenesis by promoting the browning of adipocytes. Myokines, osteokines, and adipokines exert autocrine/paracrine effects locally as well as through the endocrine system, to regulate muscle, bone, and fat metabolism. Reductions in physical activity and increases in energy intake, both linked with aging, leads to adipocyte hypertrophy and the recruitment of immunological cells (macrophages). In turn, this releases pro-inflammatory adipokines which induces chronic low-grade inflammation (LGI), a key player in the pathology of several diseases. However, exercise-induced stimulation of bioactive cytokines, through muscle-bone-fat crosstalk, increases muscle anabolism, bone formation, mitochondrial biogenesis, glucose utilization, and fatty acid oxidation, and attenuates chronic LGI.

Musculoskeletal Health in the Context of Spinal Cord Injury.

PURPOSE OF REVIEW: This review assembles recent understanding of the profound loss of muscle and bone in spinal cord injury (SCI). It is important to try to understand these changes, and the context in which they occur, because of their impact on the wellbeing of SC-injured individuals, and the urgent need for viable preventative therapies. RECENT FINDINGS: Recent research provides new understanding of the effects of age and systemic factors on the response of bone to loading, of relevance to attempts to provide load therapy for bone in SCI. The rapidly growing dataset describing the biochemical crosstalk between bone and muscle, and the cell and molecular biology of myokines signalling to bone and osteokines regulating muscle metabolism and mass, is reviewed. The ways in which this crosstalk may be altered in SCI is summarised. Therapeutic approaches to the catabolic changes in muscle and bone in SCI require a holistic understanding of their unique mechanical and biochemical context.

Emerging Role of Non-collagenous Bone Proteins as Osteokines in Extraosseous Tissues.

Bone is a unique tissue, composed of various types of cells embedded in a calcified extracellular matrix (ECM), whose dynamic structure consists of organic and inorganic compounds produced by bone cells. The main inorganic component is represented by hydroxyapatite, whilst the organic ECM is primarily made up of type I collagen and non-collagenous proteins. These proteins play an important role in bone homeostasis, calcium regulation, and maintenance of the hematopoietic niche. Recent advances in bone biology have highlighted the importance of specific bone proteins, named "osteokines", possessing endocrine functions and exerting effects on nonosseous tissues. Accordingly, osteokines have been found to act as growth factors, cell receptors, and adhesion molecules, thus modifying the view of bone from a static tissue fulfilling mobility to an endocrine organ itself. Since bone is involved in a paracrine and endocrine cross-talk with other tissues, a better understanding of bone secretome and the systemic roles of osteokines is expected to provide benefits in multiple topics: such as identification of novel biomarkers and the development of new therapeutic strategies. The present review discusses in detail the known osseous and extraosseous effects of these proteins and the possible respective clinical and therapeutic significance.

Bone-organ axes: bidirectional crosstalk.

In addition to its recognized role in providing structural support, bone plays a crucial role in maintaining the functionality and balance of various organs by secreting specific cytokines (also known as osteokines). This reciprocal influence extends to these organs modulating bone homeostasis and development, although this aspect has yet to be systematically reviewed. This review aims to elucidate this bidirectional crosstalk, with a particular focus on the role of osteokines. Additionally, it presents a unique compilation of evidence highlighting the critical function of extracellular vesicles (EVs) within bone-organ axes for the first time. Moreover, it explores the implications of this crosstalk for designing and implementing bone-on-chips and assembloids, underscoring the importance of comprehending these interactions for advancing physiologically relevant in vitro models. Consequently, this review establishes a robust theoretical foundation for preventing, diagnosing, and treating diseases related to the bone-organ axis from the perspective of cytokines, EVs, hormones, and metabolites.

Osteokines in Nonalcoholic Fatty Liver Disease.

PURPOSE OF REVIEW: To critically summarize evidence on the potential role of osteokines in the pathogenesis and progression of nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: There are emerging data supporting that certain osteokines, which are specific bone-derived proteins, may beneficially or adversely affect hepatic metabolism, and their alterations in the setting of osteoporosis or other bone metabolic diseases may possibly contribute to the development and progression of NAFLD. There is evidence showing a potential bidirectional association between NAFLD and bone metabolism, which may imply the existence of a liver-bone axis. In this regard, osteocalcin, osteoprotegerin, bone morphogenic protein 4 (BMP4) and BMP6 appear to have a positive impact on the liver, thus possibly alleviating NAFLD, whereas osteopontin, receptor activator of nuclear factor kappa Β ligand (RANKL), sclerostin, periostin, BMP8B, and fibroblast growth factor 23 (FGF23) appear to have a negative impact on the liver, thus possibly exacerbating NAFLD. The potential implication of osteokines in NAFLD warrants further animal and clinical research in the field that may possibly result in novel therapeutic targets for NAFLD in the future.

Muscle-bone crosstalk via endocrine signals and potential targets for osteosarcopenia-related fracture.

Background: Osteosarcopenia is a syndrome coexisting sarcopenia and osteopenia/osteoporosis, with a high fracture risk. Recently, skeletal muscle and bone have been recognized as endocrine organs capable of communication through secreting myokines and osteokines, respectively. With a deeper understanding of the muscle-bone crosstalk, these endocrine signals exhibit an important role in osteosarcopenia development and fracture healing. Methods: This review summarizes the role of myokines and osteokines in the development and treatment of osteosarcopenia and fracture, and discusses their potential for osteosarcopenia-related fracture treatment. Results: Several well-defined myokines (myostatin and irisin) and osteokines (RANKL and SOST) are found to not only regulate skeletal muscle and bone metabolism but also influence fracture healing processes. Systemic interventions targeting these biochemical signals has shown promising results in improving the mass and functions of skeletal muscle and bone, as well as accelerating fracture healing processes. Conclusion: The regulation of muscle-bone crosstalk via biochemical signals presents a novel and promising strategy for treating osteosarcopenia and fracture by simultaneously enhancing bone and muscle anabolism. We propose that myostatin, irisin, RANKL, and SOST may serve as potential targets to treat fracture patients with osteosarcopenia. The translational potential of this article: Osteosarcopenia is an emerging geriatric syndrome where sarcopenia and osteoporosis coexist, with high fracture risk, delayed fracture healing, and increased mortality. However, no pharmacological agent is available to treat fracture patients with osteosarcopenia. This review summarizes the role of several myokines and osteokines in the development and treatment of osteosacropenia and fracture, as well as discusses their potential as intervention targets for osteosarcopenia-related fracture, which provides a novel and promising strategy for future osteosarcopenia-related fracture treatment.

Crosstalk between bone and muscle in chronic kidney disease.

With increasing life expectancy, the related disorders of bone loss, metabolic dysregulation and sarcopenia have become major health threats to the elderly. Each of these conditions is prevalent in patients with chronic kidney disease (CKD), particularly in more advanced stages. Our current understanding of the bone-muscle interaction is beyond mechanical coupling, where bone and muscle have been identified as interrelated secretory organs, and regulation of both bone and muscle metabolism occurs through osteokines and myokines via autocrine, paracrine and endocrine systems. This review appraises the current knowledge regarding biochemical crosstalk between bone and muscle, and considers recent progress related to the role of osteokines and myokines in CKD, including modulatory effects of physical exercise and potential therapeutic targets to improve musculoskeletal health in CKD patients.

Serum Osteocalcin, Sclerostin and Lipocalin-2 Levels in Adolescent Boys with Obesity over a 12-Week Sprint Interval Training.

The aim of the study was to examine the effects of supervised cycling sprint interval training (SIT) on serum osteocalcin, lipocalin-2 and sclerostin levels, and bone mineral characteristics among obese adolescent boys. Untrained obese adolescent boys aged 13.4 ± 0.3 were assigned to either a 12-week SIT group (3 sessions/week), or a non-exercising control group who continued with their habitual everyday life. Serum osteocalcin, lipocalin-2 and sclerostin concentrations, and bone mineral values were assessed before and after intervention. After 12-week intervention, where 14 boys in both groups ended the study, there were no significant differences in serum osteokine levels between the groups after 12 weeks, while whole body bone mineral content and lower limb bone mineral density increased in the SIT group (p < 0.05). Change in body mass index was negatively correlated with the change in osteocalcin (r = -0.57; p = 0.034), and positively correlated with the change in lipocalin-2 levels (r = 0.57; p = 0.035) in the SIT group. Supervised 12-week SIT intervention improved bone mineral characteristics, but did not change osteocalcin, lipocalin-2 or sclerostin levels in adolescent boys with obesity.

Interplay between Cultured Human Osteoblastic and Skeletal Muscle Cells: Effects of Conditioned Media on Glucose and Fatty Acid Metabolism.

The interplay between skeletal muscle and bone is primarily mechanical; however, biochemical crosstalk by secreted mediators has recently gained increased attention. The aim of this study was to investigate metabolic effects of conditioned medium from osteoblasts (OB-CM) on myotubes and vice versa. Human skeletal muscle cells incubated with OB-CM showed increased glucose uptake and oxidation, and mRNA expression of the glucose transporter (GLUT) 1, while fatty acid uptake and oxidation, and mRNA expression of the fatty acid transporter CD36 were decreased. This was supported by proteomic analysis, where expression of proteins involved in glucose uptake, glycolytic pathways, and the TCA cycle were enhanced, and expression of several proteins involved in fatty acid metabolism were reduced. Similar effects on energy metabolism were observed in human bone marrow stromal cells differentiated to osteoblastic cells incubated with conditioned medium from myotubes (SKM-CM), with increased glucose uptake and reduced oleic acid uptake. Proteomic analyses of the two conditioned media revealed many common proteins. Thus, our data may indicate a shift in fuel preference from fatty acid to glucose metabolism in both cell types, induced by conditioned media from the opposite cell type, possibly indicating a more general pattern in communication between these tissues.

Organokines in COVID-19: A Systematic Review.

Coronavirus disease 2019 (COVID-19) is a viral infection caused by SARS-CoV-2 that induces a generalized inflammatory state. Organokines (adipokines, osteokines, myokines, hepatokines, and cardiokines) can produce beneficial or harmful effects in this condition. This study aimed to systematically review the role of organokines on COVID-19. PubMed, Embase, Google Scholar, and Cochrane databases were searched, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and 37 studies were selected, comprising more than 2700 individuals infected with the virus. Among COVID-19 patients, organokines have been associated with endothelial dysfunction and multiple organ failure due to augmented cytokines and increased SARS-CoV-2 viremia. Changes in the pattern of organokines secretion can directly or indirectly contribute to aggravating the infection, promoting immune response alterations, and predicting the disease progression. These molecules have the potential to be used as adjuvant biomarkers to predict the severity of the illness and severe outcomes.

The Roles of RANK/RANKL/OPG in Cardiac, Skeletal, and Smooth Muscles in Health and Disease.

Although their physiology and functions are very different, bones, skeletal and smooth muscles, as well as the heart have the same embryonic origin. Skeletal muscles and bones interact with each other to enable breathing, kinesis, and the maintenance of posture. Often, muscle and bone tissues degenerate synchronously under various conditions such as cancers, space travel, aging, prolonged bed rest, and neuromuscular diseases. In addition, bone tissue, skeletal and smooth muscles, and the heart share common signaling pathways. The RANK/RANKL/OPG pathway, which is essential for bone homeostasis, is also implicated in various physiological processes such as sarcopenia, atherosclerosis, and cardiovascular diseases. Several studies have reported bone-skeletal muscle crosstalk through the RANK/RANKL/OPG pathway. This review will summarize the current evidence indicating that the RANK/RANKL/OPG pathway is involved in muscle function. First, we will briefly discuss the role this pathway plays in bone homeostasis. Then, we will present results from various sources indicating that it plays a physiopathological role in skeletal, smooth muscle, and cardiac functions. Understanding how the RANK/RANKL/OPG pathway interferes in several physiological disorders may lead to new therapeutic approaches aimed at protecting bones and other tissues with a single treatment.

Crosstalk between bone and other organs.

Bone has long been considered as a silent organ that provides a reservoir of calcium and phosphorus, traditionally. Recently, further study of bone has revealed additional functions as an endocrine organ connecting systemic organs of the whole body. Communication between bone and other organs participates in most physiological and pathological events and is responsible for the maintenance of homeostasis. Here, we present an overview of the crosstalk between bone and other organs. Furthermore, we describe the factors mediating the crosstalk and review the mechanisms in the development of potential associated diseases. These connections shed new light on the pathogenesis of systemic diseases and provide novel potential targets for the treatment of systemic diseases.

Muscle-Bone Crosstalk in Chronic Obstructive Pulmonary Disease.

Sarcopenia and osteoporosis are common musculoskeletal comorbidities of chronic obstructive pulmonary disease (COPD) that seriously affect the quality of life and prognosis of the patient. In addition to spatially mechanical interactions, muscle and bone can also serve as endocrine organs by producing myokines and osteokines to regulate muscle and bone functions, respectively. As positive and negative regulators of skeletal muscles, the myokines irisin and myostatin not only promote/inhibit the differentiation and growth of skeletal muscles, but also regulate bone metabolism. Both irisin and myostatin have been shown to be dysregulated and associated with exercise and skeletal muscle dysfunction in COPD. During exercise, skeletal muscles produce a large amount of IL-6 which acts as a myokine, exerting at least two different conflicting functions depending on physiological or pathological conditions. Remarkably, IL-6 is highly expressed in COPD, and considered to be a biomarker of systemic inflammation, which is associated with both sarcopenia and bone loss. For osteokines, receptor activator of nuclear factor kappa-B ligand (RANKL), a classical regulator of bone metabolism, was recently found to play a critical role in skeletal muscle atrophy induced by chronic cigarette smoke (CS) exposure. In this focused review, we described evidence for myokines and osteokines in the pathogenesis of skeletal muscle dysfunction/sarcopenia and osteoporosis in COPD, and proposed muscle-bone crosstalk as an important mechanism underlying the coexistence of muscle and bone diseases in COPD.