Understanding osteokine biology.

Bone is an endocrine organ that participates in whole-body homeostasis. The biology of bone-derived osteokines, however, remains unclear. Liang et al. integrate experimental and computational methods to discover new osteokines, establish their cell of origin and target site, and study their role in aging and during mechanical stress.

Fluorinated hydroxyapatite conditions a favorable osteo-immune microenvironment via triggering metabolic shift from glycolysis to oxidative phosphorylation.

BACKGROUND: Biological-derived hydroxyapatite is widely used as a bone substitute for addressing bone defects, but its limited osteoconductive properties necessitate further improvement. The osteo-immunomodulatory properties hold crucial promise in maintaining bone homeostasis, and precise modulation of macrophage polarization is essential in this process. Metabolism serves as a guiding force for immunity, and fluoride modification represents a promising strategy for modulating the osteoimmunological environment by regulating immunometabolism. In this context, we synthesized fluorinated porcine hydroxyapatite (FPHA), and has demonstrated its enhanced biological properties and osteogenic capacity. However, it remains unknown whether and how FPHA affects the immune microenvironment of the bone defects. METHODS: FPHA was synthesized and its composition and structural properties were confirmed. Macrophages were cultured with FPHA extract to investigate the effects of FPHA on their polarization and the related osteo-immune microenvironment. Furthermore, total RNA of these macrophages was extracted, and RNA-seq analysis was performed to explore the underlying mechanisms associated with the observed changes in macrophages. The metabolic states were evaluated with a Seahorse analyzer. Additionally, immunohistochemical staining was performed to evaluate the macrophages response after implantation of the novel bone substitutes in critical size calvarial defects in SD rats. RESULTS: The incorporation of fluoride ions in FPHA was validated. FPHA promoted macrophage proliferation and enhanced the expression of M2 markers while suppressing the expression of M1 markers. Additionally, FPHA inhibited the expression of inflammatory factors and upregulated the expression of osteogenic factors, thereby enhancing the osteogenic differentiation capacity of the rBMSCs. RNA-seq analysis suggested that the polarization-regulating function of FPHA may be related to changes in cellular metabolism. Further experiments confirmed that FPHA enhanced mitochondrial function and promoted the metabolic shift of macrophages from glycolysis to oxidative phosphorylation. Moreover, in vivo experiments validated the above results in the calvarial defect model in SD rats. CONCLUSION: In summary, our study reveals that FPHA induces a metabolic shift in macrophages from glycolysis to oxidative phosphorylation. This shift leads to an increased tendency toward M2 polarization in macrophages, consequently creating a favorable osteo-immune microenvironment. These findings provide valuable insights into the impact of incorporating an appropriate concentration of fluoride on immunometabolism and macrophage mitochondrial function, which have important implications for the development of fluoride-modified immunometabolism-based bone regenerative biomaterials and the clinical application of FPHA or other fluoride-containing materials.

Chromium nanoparticles improve bone turnover regulation in rats fed a high-fat, low-fibre diet.

The aim of the study was to investigate the effect of returning to a balanced diet combined with chromium picolinate (CrPic) or chromium nanoparticles (CrNPs) supplementation at a pharmacologically relevant dose of 0.3 mg/kg body weight on the expression level of selected genes and bone turnover markers in the blood and bones of rats fed an obese diet. The results of the study showed that chronic intake of a high-fat obesogenic diet negatively affects bone turnover by impairing processes of both synthesis and degradation of bones. The switch to a healthy diet proved insufficient to regulate bone metabolism disorders induced by an obesogenic diet, even when it was supplemented with chromium, irrespective of its form. Supplementation with CrPic with no change in diet stimulated bone metabolism only at the molecular level, towards increased osteoclastogenesis (bone resorption). In contrast, CrNPs added to the high-fat diet effectively regulated bone turnover by increasing both osteoblastogenesis and osteoclastogenesis, with these changes directed more towards bone formation. The results of the study suggest that unfavourable changes in bone metabolism induced by chronic intake of a high-fat diet can be mitigated by supplementation with CrNPs, whereas a change in eating habits fails to achieve a similar effect.

Proteomic Insights into Osteoporosis: Unraveling Diagnostic Markers of and Therapeutic Targets for the Metabolic Bone Disease.

Osteoporosis (OP), a prevalent skeletal disorder characterized by compromised bone strength and increased susceptibility to fractures, poses a significant public health concern. This review aims to provide a comprehensive analysis of the current state of research in the field, focusing on the application of proteomic techniques to elucidate diagnostic markers and therapeutic targets for OP. The integration of cutting-edge proteomic technologies has enabled the identification and quantification of proteins associated with bone metabolism, leading to a deeper understanding of the molecular mechanisms underlying OP. In this review, we systematically examine recent advancements in proteomic studies related to OP, emphasizing the identification of potential biomarkers for OP diagnosis and the discovery of novel therapeutic targets. Additionally, we discuss the challenges and future directions in the field, highlighting the potential impact of proteomic research in transforming the landscape of OP diagnosis and treatment.

Concentrations of Bioelements (Zn, Cu, Fe, Cr, Mg, Mn) in Serum and Bone Tissue of Aging Men Undergoing Hip Arthroplasty: Implications for Erectile Dysfunction.

Background: Erectile dysfunction (ED) stands out as one of the most prevalent sexual disorders in men, with its incidence progressively escalating with age. As delineated by the International Consultation Committee for Sexual Medicine on Definitions/Epidemiology/Risk Factors for Sexual Dysfunction, the prevalence of ED among men under 40 years is estimated to be within the range of 1-10%. The aim of this study was to determine the relationship between the concentration of bioelements (Zn, Cu, Fe, Cr, Mg, and Mn) in the serum and bone tissue and the concentration of selected hormones in men with and without erectile dysfunction. Materials and methods: The retrospective cohort study included 152 men who underwent total hip arthroplasty for hip osteoarthritis at the Department of Orthopaedic Traumatology and Musculoskeletal Oncology at the Pomeranian Medical University in Szczecin. Certain exclusion criteria were applied to ensure the integrity of the study. These included individuals with diabetes, a history of cancer, alcohol abuse, liver or kidney failure, New York Heart Association (NYHA) class III or IV heart failure, and those taking medications that affect bone metabolism, such as mineral supplements, neuroleptics, chemotherapeutic agents, immunosuppressants, corticosteroids, or antidepressants. Patients with hypogonadism or infertility were excluded from the study. Results: The study showed an association between bioT concentrations and Cu concentrations in both patients with and without erectile dysfunction. A correlation between bioactive testosterone and Cr concentrations was also observed in both groups. Patients with erectile dysfunction showed a relationship between bioT concentration and Zn concentration, TT concentration and Mn concentration, FT concentration and Zn concentration, and E2 concentration and Cr concentration. An analysis of elemental concentrations in bone tissue showed an association between FT and Mg and Mn concentrations, but only in patients with erectile dysfunction. In patients without erectile dysfunction, a correlation was observed between FT and Cu concentrations. A correlation was also observed between bioT concentrations and Mg, Mn, and Zn concentrations, but only in patients with erectile dysfunction. In patients without erectile dysfunction, a correlation was observed between bioT and Cu concentrations. Conclusions: Studying the relationship between the concentration of bioelements (Zn, Cu, Fe, Cr, Mg, and Mn) in the serum and bone tissue and the concentration of selected hormones in men may be important in explaining the etiology of the problem. The study of the concentration of Zn and Cu in bone tissue and serum showed that these two elements, regardless of the place of accumulation, may be related to the concentration of androgens in men.

Bone and Extracellular Signal-Related Kinase 5 (ERK5).

Bones are vital for anchoring muscles, tendons, and ligaments, serving as a fundamental element of the human skeletal structure. However, our understanding of bone development mechanisms and the maintenance of bone homeostasis is still limited. Extracellular signal-related kinase 5 (ERK5), a recently identified member of the mitogen-activated protein kinase (MAPK) family, plays a critical role in the pathogenesis and progression of various diseases, especially neoplasms. Recent studies have highlighted ERK5's significant role in both bone development and bone-associated pathologies. This review offers a detailed examination of the latest research on ERK5 in different tissues and diseases, with a particular focus on its implications for bone health. It also examines therapeutic strategies and future research avenues targeting ERK5.

Methods to Enable Spatial Transcriptomics of Bone Tissues.

Understanding the relationship between the cells and their location within each tissue is critical to uncover the biological processes associated with normal development and disease pathology. Spatial transcriptomics is a powerful method that enables the analysis of the whole transcriptome within tissue samples, thus providing information about the cellular gene expression and the histological context in which the cells reside. While this method has been extensively utilized for many soft tissues, its application for the analyses of hard tissues such as bone has been challenging. The major challenge resides in the inability to preserve good quality RNA and tissue morphology while processing the hard tissue samples for sectioning. Therefore, a method is described here to process freshly obtained bone tissue samples to effectively generate spatial transcriptomics data. The method allows for the decalcification of the samples, granting successful tissue sections with preserved morphological details while avoiding RNA degradation. In addition, detailed guidelines are provided for samples that were previously paraffin-embedded, without demineralization, such as samples collected from tissue banks. Using these guidelines, high-quality spatial transcriptomics data generated from tissue bank samples of primary tumor and lung metastasis of bone osteosarcoma are shown.

Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation.

CONTEXT: Chronic kidney disease (CKD) leads to alterations in fibroblast growth factor 23 (FGF23) and the renal-bone axis. This may be partly driven by altered inflammation and iron status. Vitamin D supplementation may reduce inflammation. OBJECTIVE AND METHODS: Older adults with early CKD (estimated glomerular filtration rate (eGFR) 30-60 ml/min/1.73 m2; CKDG3a/b; n = 35) or normal renal function (eGFR >90 ml/min/1.73 m2; CKDG1; n = 35) received 12,000, 24,000 or 48,000 IU D3/month for 1 year. Markers of the renal-bone axis, inflammation and iron status were investigated pre- and post-supplementation. Predictors of c-terminal and intact FGF23 (cFGF23; iFGF23) were identified by univariate and multivariate regression. RESULTS: Pre-supplementation, comparing CKDG3a/b to CKDG1, plasma cFGF23, iFGF23, PTH, sclerostin and TNFα were significantly higher and Klotho, 1,25-dihydroxyvitamin D and iron were lower. Post-supplementation, only cFGF23, 25(OH)D and IL6 differed between groups. The response to supplementation differed between eGFR groups. Only in the CKDG1 group, phosphate decreased, cFGF23, iFGF23 and procollagen type I N-propeptide increased. In the CKDG3a/b group, TNFα significantly decreased, and iron increased. Plasma 25(OH)D and IL10 increased, and carboxy-terminal collagen crosslinks decreased in both groups. In univariate models cFGF23 and iFGF23 were predicted by eGFR and regulators of calcium and phosphate metabolism at both time points; IL6 predicted cFGF23 (post-supplementation) and iFGF23 (pre-supplementation) in univariate models. Hepcidin predicted post-supplementation cFGF23 in multivariate models with eGFR. CONCLUSION: Alterations in regulators of the renal-bone axis, inflammation and iron status were found in early CKD. The response to vitamin D3 supplementation differed between eGFR groups. Plasma IL6 predicted both cFGF23 and iFGF23 and hepcidin predicted cFGF23.

Vitamin D and bone health: What vitamin D can and cannot do.

Historically vitamin D deficiency had devastating consequences for children causing rickets resulting in severe bone deformities often leading to death. The mystery of the cause of rickets finally came to light when it was observed that cod liver oil and sunlight could prevent and cure rickets. The first vitamin D to be discovered was vitamin D2 from ergosterol in ultraviolet irradiated yeast. Vitamin D3 was discovered from UV exposure to the skin. Investigations revealed the two major functions of vitamin D were to increase intestinal calcium and phosphate absorption and mobilize calcium from the skeleton to maintain calcium and phosphorus homeostasis. Later studies demonstrated that vitamin D does not have an active role in bone mineralization. Vitamin D deficiency results in secondary hyperparathyroidism increasing bone resorption. As a result, this decreases bone mineral content and compromises the architectural integrity increasing risk for fracture. Vitamin D deficiency has also been shown to enhance aging of the bone causing cracks and enhancing bone fractures. Vitamin D deficiency also causes osteomalacia. Therefore, vitamin D sufficiency is extremely important to maximize bone health throughout life. It helps to prevent bone loss, but it cannot restore bone loss due to increased bone resorption that can occur under a variety of circumstances including menopause. The Endocrine Society Guidelines recommends for all ages that adequate vitamin D obtained from the sun, foods and supplements is necessary in order to maintain a circulating concentration of 25-hydroxyvitamin D of at least 30 ng/mL for maximum bone health.

[Transcriptomic characteristics analysis of bone from chronic osteomyelitis].

OBJECTIVE: To explore the molecular mechanism of chronic osteomyelitis and to clarify the role of MAPK signal pathway in the pathogenesis of chronic osteomyelitis, by collecting and analyzing the transcriptional information of bone tissue in patients with chronic osteomyelitis. METHODS: Four cases of traumatic osteomyelitis in limbs from June 2019 to June 2020 were selected, and the samples of necrotic osteonecrosis from chronic osteomyelitis (necrotic group), and normal bone tissue (control group) were collected. Transcriptome information was collected by Illumina Hiseq Xten high throughput sequencing platform, and the gene expression in bone tissue was calculated by FPKM. The differentially expressed genes were screened by comparing the transcripts of the Necrotic group and control group. Genes were enriched by GO and KEGG. MAP3K7 and NFATC1 were selected as differential targets in the verification experiments, by using rat osteomyelitis animal model and immunohistochemical analysis. RESULTS: A total of 5548 differentially expressed genes were obtained by high throughput sequencing by comparing the necrotic group and control group, including 2701 up-regulated and 2847 down-regulated genes. The genes enriched in MAPK pathway and osteoclast differentiation pathway were screened, the common genes expressed in both MAPK and osteoclast differentiation pathway were (inhibitor of nuclear factor κ subunit Beta, IκBKß), (mitogen-activated protein kinase 7, MAP3K7), (nuclear factor of activated t cells 1, NFATC1) and (nuclear factor Kappa B subunit 2, NFκB2). In rat osteomyelitis model, MAP3K7 and NFATC1 were highly expressed in bone marrow and injured bone tissue. CONCLUSION: Based on the transcriptome analysis, the MAPK signaling and osteoclast differentiation pathways were closely related to chronic osteomyelitis, and the key genes IκBKß, MAP3K7, NFATC1, NFκB2 might be new targets for clinical diagnosis and therapy of chronic osteomyelitis.

O-GlcNAcylation: roles and potential therapeutic target for bone pathophysiology.

O-linked N-acetylglucosamine (O-GlcNAc) protein modification (O-GlcNAcylation) is a critical post-translational modification (PTM) of cytoplasmic and nuclear proteins. O-GlcNAcylation levels are regulated by the activity of two enzymes, O-GlcNAc transferase (OGT) and O­GlcNAcase (OGA). While OGT attaches O-GlcNAc to proteins, OGA removes O-GlcNAc from proteins. Since its discovery, researchers have demonstrated O-GlcNAcylation on thousands of proteins implicated in numerous different biological processes. Moreover, dysregulation of O-GlcNAcylation has been associated with several pathologies, including cancers, ischemia-reperfusion injury, and neurodegenerative diseases. In this review, we focus on progress in our understanding of the role of O-GlcNAcylation in bone pathophysiology, and we discuss the potential molecular mechanisms of O-GlcNAcylation modulation of bone-related diseases. In addition, we explore significant advances in the identification of O-GlcNAcylation-related regulators as potential therapeutic targets, providing novel therapeutic strategies for the treatment of bone-related disorders.

Role of epigenetic regulatory mechanisms in age-related bone homeostasis imbalance.

Alterations to the human organism that are brought about by aging are comprehensive and detrimental. Of these, an imbalance in bone homeostasis is a major outward manifestation of aging. In older adults, the decreased osteogenic activity of bone marrow mesenchymal stem cells and the inhibition of bone marrow mesenchymal stem cell differentiation lead to decreased bone mass, increased risk of fracture, and impaired bone injury healing. In the past decades, numerous studies have reported the epigenetic alterations that occur during aging, such as decreased core histones, altered DNA methylation patterns, and abnormalities in noncoding RNAs, which ultimately lead to genomic abnormalities and affect the expression of downstream signaling osteoporosis treatment and promoter of fracture healing in older adults. The current review summarizes the impact of epigenetic regulation mechanisms on age-related bone homeostasis imbalance.

Hypertonic saline- and detergent-accelerated EDTA-based decalcification better preserves mRNA of bones.

Ethylenediaminetetraacetic acid (EDTA), a classically used chelating agent of decalcification, maintains good morphological details, but its slow decalcification limits its wider applications. Many procedures have been reported to accelerate EDTA-based decalcification, involving temperature, concentration, sonication, agitation, vacuum, microwave, or combination. However, these procedures, concentrating on purely tissue-outside physical factors to increase the chemical diffusion, do not enable EDTA to exert its full capacity due to tissue intrinsic chemical resistances around the diffusion passage. The resistances, such as tissue inner lipids and electric charges, impede the penetration of EDTA. We hypothesized that delipidation and shielding electric charges would accelerate EDTA-based penetration and the subsequent decalcification. The hypothesis was verified by the observation of speedy penetration of EDTA with additives of detergents and hypertonic saline, testing on tissue-mimicking gels of collagen and adult mouse bones. Using a 26% EDTA mixture with the additives at 45°C, a conventional 7-day decalcification of adult mouse ankle joints could be completed within 24 h while the tissue morphological structure, antigenicity, enzymes, and DNA were well preserved, and mRNA better retained compared to using 15% EDTA at room temperature. The addition of hypertonic saline and detergents to EDTA decalcification is a simple, rapid, and inexpensive method that doesn't disrupt the current histological workflow. This method is equally or even more effective than the currently most used decalcification methods in preserving the morphological details of tissues. It can be highly beneficial for the related community.

Bone aluminum accumulation in the current era.

In the last few years, evidence from the Brazilian Registry of Bone Biopsy (REBRABO) has pointed out a high incidence of aluminum (Al) accumulation in the bones of patients with CKD under dialysis. This surprising finding does not appear to be merely a passive metal accumulation, as prospective data from REBRABO suggest that the presence of Al in bone may be independently associated with major adverse cardiovascular events. This information contrasts with the perception of epidemiologic control of this condition around the world. In this opinion paper, we discussed why the diagnosis of Al accumulation in bone is not reported in other parts of the world. We also discuss a range of possibilities to understand why bone Al accumulation still occurs, not as a classical syndrome with systemic signs of intoxication, as occurred it has in the past.

Vitamin A - discovery, metabolism, receptor signaling and effects on bone mass and fracture susceptibility.

The first evidence of the existence of vitamin A was the observation 1881 that a substance present in small amounts in milk was necessary for normal development and life. It was not until more than 100 years later that it was understood that vitamin A acts as a hormone through nuclear receptors. Unlike classical hormones, vitamin A cannot be synthesized by the body but needs to be supplied by the food as retinyl esters in animal products and ß-carotene in vegetables and fruits. Globally, vitamin A deficiency is a huge health problem, but in the industrialized world excess of vitamin A has been suggested to be a risk factor for secondary osteoporosis and enhanced susceptibility to fractures. Preclinical studies unequivocally have shown that increased amounts of vitamin A cause decreased cortical bone mass and weaker bones due to enhanced periosteal bone resorption. Initial clinical studies demonstrated a negative association between intake of vitamin A, as well as serum levels of vitamin A, and bone mass and fracture susceptibility. In some studies, these observations have been confirmed, but in other studies no such associations have been observed. One meta-analysis found that both low and high serum levels of vitamin A were associated with increased relative risk of hip fractures. Another meta-analysis also found that low levels of serum vitamin A increased the risk for hip fracture but could not find any association with high serum levels of vitamin A and hip fracture. It is apparent that more clinical studies, including large numbers of incident fractures, are needed to determine which levels of vitamin A that are harmful or beneficial for bone mass and fracture. It is the aim of the present review to describe how vitamin A was discovered and how vitamin A is absorbed, metabolized and is acting as a ligand for nuclear receptors. The effects by vitamin A in preclinical studies are summarized and the clinical investigations studying the effect by vitamin A on bone mass and fracture susceptibility are discussed in detail.

Circadian Regulation of Bone Remodeling.

Adult bones are continuously remodeled by the balance between bone resorption by osteoclasts and subsequent bone formation by osteoblasts. Many studies have provided molecular evidence that bone remodeling is under the control of circadian rhythms. Circadian fluctuations have been reported in the serum and urine levels of bone turnover markers, such as digested collagen fragments and bone alkaline phosphatase. Additionally, the expressions of over a quarter of all transcripts in bones show circadian rhythmicity, including the genes encoding master transcription factors for osteoblastogenesis and osteoclastogenesis, osteogenic cytokines, and signaling pathway proteins. Serum levels of calcium, phosphate, parathyroid hormone, and calcitonin also display circadian rhythmicity. Finally, osteoblast- and osteoclast-specific knockout mice targeting the core circadian regulator gene Bmal1 show disrupted bone remodeling, although the results have not always been consistent. Despite these studies, however, establishing a direct link between circadian rhythms and bone remodeling in vivo remains a major challenge. It is nearly impossible to repeatedly collect bone materials from human subjects while following circadian changes. In addition, the differences in circadian gene regulation between diurnal humans and nocturnal mice, the main model organism, remain unclear. Filling the knowledge gap in the circadian regulation of bone remodeling could reveal novel regulatory mechanisms underlying many bone disorders including osteoporosis, genetic diseases, and fracture healing. This is also an important question for the basic understanding of how cell differentiation progresses under the influence of cyclically fluctuating environments.

Links among Obesity, Type 2 Diabetes Mellitus, and Osteoporosis: Bone as a Target.

Obesity, type 2 diabetes mellitus (T2DM) and osteoporosis are serious diseases with an ever-increasing incidence that quite often coexist, especially in the elderly. Individuals with obesity and T2DM have impaired bone quality and an elevated risk of fragility fractures, despite higher and/or unchanged bone mineral density (BMD). The effect of obesity on fracture risk is site-specific, with reduced risk for several fractures (e.g., hip, pelvis, and wrist) and increased risk for others (e.g., humerus, ankle, upper leg, elbow, vertebrae, and rib). Patients with T2DM have a greater risk of hip, upper leg, foot, humerus, and total fractures. A chronic pro-inflammatory state, increased risk of falls, secondary complications, and pharmacotherapy can contribute to the pathophysiology of aforementioned fractures. Bisphosphonates and denosumab significantly reduced the risk of vertebral fractures in patients with both obesity and T2DM. Teriparatide significantly lowered non-vertebral fracture risk in T2DM subjects. It is important to recognize elevated fracture risk and osteoporosis in obese and T2DM patients, as they are currently considered low risk and tend to be underdiagnosed and undertreated. The implementation of better diagnostic tools, including trabecular bone score, lumbar spine BMD/body mass index (BMI) ratio, and microRNAs to predict bone fragility, could improve fracture prevention in this patient group.

Natural Compounds for Bone Remodeling: A Computational and Experimental Approach Targeting Bone Metabolism-Related Proteins.

Osteoporosis, characterized by reduced bone density and increased fracture risk, affects over 200 million people worldwide, predominantly older adults and postmenopausal women. The disruption of the balance between bone-forming osteoblasts and bone-resorbing osteoclasts underlies osteoporosis pathophysiology. Standard treatment includes lifestyle modifications, calcium and vitamin D supplementation and specific drugs that either inhibit osteoclasts or stimulate osteoblasts. However, these treatments have limitations, including side effects and compliance issues. Natural products have emerged as potential osteoporosis therapeutics, but their mechanisms of action remain poorly understood. In this study, we investigate the efficacy of natural compounds in modulating molecular targets relevant to osteoporosis, focusing on the Mitogen-Activated Protein Kinase (MAPK) pathway and the gut microbiome's influence on bone homeostasis. Using an in silico and in vitro methodology, we have identified quercetin as a promising candidate in modulating MAPK activity, offering a potential therapeutic perspective for osteoporosis treatment.

SIRT1 maintains bone homeostasis by regulating osteoblast glycolysis through GOT1.

The silent information regulator T1 (SIRT1) is linked to longevity and is a crucial mediator of osteoblast function. We investigated the direct role of Sirt1 during bone modeling and remodeling stages in vivo using Tamoxifen-inducible osteoblast-specific Sirt1 conditional knockout (cKO) mice. cKO mice exhibited lower trabecular and cortical bone mass in the distal femur. These phenotypes were coupled with lower bone formation and bone resorption. Metabolomics analysis revealed that the metabolites involved in glycolysis were significantly decreased in cKO mice. Further analysis of the quantitative acetylome revealed 11 proteins with upregulated acetylation levels in both the femur and calvaria of cKO mice. Cross-analysis identified four proteins with the same upregulated lysine acetylation site in both the femur and calvaria of cKO mice. A combined analysis of the metabolome and acetylome, as well as immunoprecipitation, gene knockout, and site-mutation experiments, revealed that Sirt1 deletion inhibited glycolysis by directly binding to and increasing the acetylation level of Glutamine oxaloacetic transaminase 1 (GOT1). In conclusion, our study suggested that Sirt1 played a crucial role in regulating osteoblast metabolism to maintain bone homeostasis through its deacetylase activity on GOT1. These findings provided a novel insight into the potential targeting of osteoblast metabolism for the treatment of bone-related diseases.

Non-Classical Effects of FGF23: Molecular and Clinical Features.

This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate-calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.