Unveiling the role of osteoblastic micro RNAs in the skeleton: from biological functions to therapeutic potential / Rol de los micro-ARN osteoblásticos en el esqueleto: desde las funciones biológicas al potencial terapéutico

MicroRNAs (miRNAs) are small non-coding RNA molecules that play critical roles in post-transcriptional gene regulation. They function by binding to target messenger RNA (mRNA) molecules, leading to their degradation or inhibiting their translation into proteins. In the context of skeletal diseases, such as osteoporosis, osteoarthritis, and bone metastasis, there is growing evidence osteoblastic miRNAs, are involved in the regulation of bone formation and maintenance.Osteoblasts are bone-forming cells responsible for synthesizing and depositing the extracellular matrix, which ultimately mineralizes to form bone tissue. Osteoblastic miRNAs modulate various aspects of osteoblast function, including proliferation, differentiation, mineralization, and apoptosis. Dysregulation of these miRNAs can disrupt the balance between bone formation and resorption, leading to skeletal diseases.The therapeutic implications of targeting osteoblastic miRNAs in skeletal diseases are significant. Modulating the expression levels of specific miRNAs holds promise for developing novel therapeutic strategies to enhance bone formation, prevent bone loss, and promote bone regeneration. Potential therapeutic approaches include the use of synthetic miRNA mimics to restore miRNA expression in diseases associated with miRNA downregulation or the use of anti-miRNA oligonucleotides to inhibit miRNA function in diseases associated with miRNA upregulation.miRNA-based therapies are still in the early stages of development, and further research is needed to fully understand the complexity of miRNA networks. Additionally, the delivery of miRNAs to specific target tissues and cells remains a challenge that needs to be addressed for effective clinical translation. Nonetheless, targeting osteoblastic miRNAs represents a promising avenue for future therapeutic interventions in skeletal diseases. (AU)

Los micro-ARNs (miARNss) son pequeños ARN no codificantes que desempeñan un papel fundamental en la regulación génica postranscripcional. Ejercen su función al unir-se a moléculas de ARN mensajero (ARNm), promoviendo su degradación e inhibiendo su traducción en proteínas. En el contexto de las enfermedades esqueléticas, como la osteoporosis, la osteoartritis y la metástasis ósea existe evidencia de que los miARNs osteoblásticos están involucrados en la regulación de la formación y del mantenimiento óseo. Los osteoblastos son células formadoras de hueso responsables de sintetizar y depositar la matriz extracelular, que finalmente se mineraliza para formar el hueso. Los miARNs derivados de osteoblastos modulan varios aspectos de la función de estas células, incluida la proliferación, diferenciación, mineralización y la apoptosis. La desregulación de estos miARNs puede alterar el equilibrio entre la formación y la resorción ósea, lo que lleva a enfermedades óseas. Las implicaciones terapéuticas de los miARNs osteoblásticos en enfermedades esqueléticas son significativas. La modulación de los niveles de expresión de miARNs específicos es prometedora para desarrollar nuevas estrate-gias terapéuticas a fin de mejorar la formación, prevenir la pérdida y promover la regeneración ósea. Los enfoques terapéuticos potenciales incluyen el uso de miméticos de miARNs para restaurar la expresión de miARNs o el uso de oligonucleótidos anti-miARNs para inhibir su función. Las terapias basadas en miARNs aún se encuentran en las primeras etapas de desarrollo. La administración de miARNs a las células y los tejidos específicos sigue siendo un desafío para lograr una aplicación clínica eficaz. (AU)

A Review on the Molecular Mechanisms of Action of Natural Products in Preventing Bone Diseases.

The drugs used for treating bone diseases (BDs), at present, elicit hazardous side effects that include certain types of cancers and strokes, hence the ongoing quest for the discovery of alternatives with little or no side effects. Natural products (NPs), mainly of plant origin, have shown compelling promise in the treatments of BDs, with little or no side effects. However, the paucity in knowledge of the mechanisms behind their activities on bone remodeling has remained a hindrance to NPs' adoption. This review discusses the pathological development of some BDs, the NP-targeted components, and the actions exerted on bone remodeling signaling pathways (e.g., Receptor Activator of Nuclear Factor κ B-ligand (RANKL)/monocyte/macrophage colony-stimulating factor (M-CSF)/osteoprotegerin (OPG), mitogen-activated protein kinase (MAPK)s/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Kelch-like ECH-associated protein 1 (Keap-1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1), Bone Morphogenetic Protein 2 (BMP2)-Wnt/ß-catenin, PhosphatidylInositol 3-Kinase (PI3K)/protein kinase B (Akt)/Glycogen Synthase Kinase 3 Beta (GSK3ß), and other signaling pathways). Although majority of the studies on the osteoprotective properties of NPs against BDs were conducted ex vivo and mostly on animals, the use of NPs for treating human BDs and the prospects for future development remain promising.

Pharmacological Prevention and Management of Skeletal-Related Events and Bone Loss in Individuals with Cancer.

OBJECTIVE: To provide a literature review of the clinical efficacy and safety data of various pharmacological agents used to manage bone health in people affected by cancer. DATA SOURCES: Peer-reviewed articles and research publications identified from PubMed and relevant clinical guidelines were used in this evidence synthesis. CONCLUSION: Individuals with cancers such as breast and prostate cancers, multiple myeloma, and other malignancies are at a high risk of developing skeletal-related events such as bone fracture, bone metastasis, and osteoporosis. Pharmacologic agents such as bisphosphonates and RANK-L inhibitor (denosumab) are the mainstay therapy options for managing bone health in this population. IMPLICATIONS FOR NURSING PRACTICE: Nurses and nurse practitioners should be aware of the efficacy data of bisphosphonates and denosumab but also should be well-versed in the appropriate administration of these agents, potential side effect profiles, timely assessment, and interventions to optimize quality of life.

Adynamic bone disease: Revisited / Enfermedad ósea adinámica: Una revisión

The bone and mineral disorders form an integral part of the management of a chronic kidney disease (CKD) patient. Amongst various types of bone pathologies in chronic kidney disease-mineral bone disorder (CKD-MBD), the prevalence of adynamic bone disease (ABD) is increasing. The present review discusses the updated pathophysiology, risk factors, and management of this disorder. (AU)

Los trastornos óseos y minerales son una parte fundamental del tratamiento del paciente con enfermedad renal crónica (ERC). Entre los distintos tipos de patologías óseas en la enfermedad renal crónica-trastorno mineral óseo (ERC-TMO), la prevalencia de la enfermedad ósea adinámica (EOA) está aumentando. En esta revisión se analizan los datos actuales sobre la fisiopatología, los factores de riesgo y el tratamiento de este trastorno. (AU)

A comprehensive review on endemic and experimental fluorosis in sheep: Its diverse effects and prevention.

Fluoride is a natural element widely distributed in the environment and plays an important role in the growth of humans and animals. However, in many species, high concentrations of fluoride induce several problems, such as dental, skeletal, and non-skeletal fluorosis. Sheep living in endemic areas are sensitive to the chronic toxicity of fluoride, and they have been found to suffer not only from teeth and bone problems but also from other organs. Studies indicating the chronic harmful effects of fluoride on teeth, bones, blood biochemical parameters, kidney, liver, heart, reproductive system and growth in sheep have been clearly summarized in this review. Besides, this work also includes updated progress in terms of prevention or reduction of fluoride toxicity in this species.

The Impact of Diet and Physical Activity on Bone Health in Children and Adolescents.

There is growing recognition of the role of diet and physical activity in modulating bone mineral density, bone mineral content, and remodeling, which in turn can impact bone health later in life. Adequate nutrient composition could influence bone health and help to maximize peak bone mass. Therefore, children's nutrition may have lifelong consequences. Also, physical activity, adequate in volume or intensity, may have positive consequences on bone mineral content and density and may preserve bone loss in adulthood. Most of the literature that exists for children, about diet and physical activity on bone health, has been translated from studies conducted in adults. Thus, there are still many unanswered questions about what type of diet and physical activity may positively influence skeletal development. This review focuses on bone requirements in terms of nutrients and physical activity in childhood and adolescence to promote bone health. It explores the contemporary scientific literature that analyzes the impact of diet together with the typology and timing of physical activity that could be more appropriate depending on whether they are children and adolescents to assure an optimal skeleton formation. A description of the role of parathyroid hormone (PTH) and gut hormones (gastric inhibitory peptide (GIP), glucagon-like peptide (GLP)-1, and GLP-2) as potential candidates in this interaction to promote bone health is also presented.

14-3-3ζ: A suppressor of inflammatory arthritis.

Inflammatory arthritis (IA) is a common disease that affects millions of individuals worldwide. Proinflammatory events during IA pathogenesis are well studied; however, loss of protective immunity remains underexplored. Earlier, we reported that 14-3-3zeta (ζ) has a role in T-cell polarization and interleukin (IL)-17A signal transduction. Here, we demonstrate that 14-3-3ζ knockout (KO) rats develop early-onset severe arthritis in two independent models of IA, pristane-induced arthritis and collagen-induced arthritis. Arthritic 14-3-3ζ KO animals showed an increase in bone loss and immune cell infiltration in synovial joints. Induction of arthritis coincided with the loss of anti-14-3-3ζ antibodies; however, rescue experiments to supplement the 14-3-3ζ antibody by passive immunization did not suppress arthritis. Instead, 14-3-3ζ immunization during the presymptomatic phase resulted in significant suppression of arthritis in both wild-type and 14-3-3ζ KO animals. Mechanistically, 14-3-3ζ KO rats exhibited elevated inflammatory gene signatures at the messenger RNA and protein levels, particularly for IL-1ß. Furthermore, the immunization with recombinant 14-3-3ζ protein suppressed IL-1ß levels, significantly increased anti-14-3-3ζ antibody levels and collagen production, and preserved bone quality. The 14-3-3ζ protein increased collagen expression in primary rat mesenchymal cells. Together, our findings indicate that 14-3-3ζ causes immune suppression and extracellular remodeling, which lead to a previously unrecognized IA-suppressive function.

Understanding the Protective Effect of Phytate in Bone Decalcification Related-Diseases.

Myo-inositol hexaphosphate (phytate; IP6) is a natural compound that is abundant in cereals, legumes, and nuts, and it can bind to crystal surfaces and disturb crystal development, acting as crystallization inhibitor. The adsorption of such inhibitors to crystal faces can also inhibit crystal dissolution. The binding of phytate to metal cofactors suggests that it could be used for treatment of osteoporosis. Our in-vitro study showed that phytate inhibits dissolution of hydroxyapatite (HAP). The effect of phytate was similar to that of alendronate and greater than that of etidronate. This led us to perform a cross-sectional study to investigate the impact of consumption of IP6 on bone mineral density (BMD) in post-menopausal women. Our data indicate that BMD and t-score of lumbar spine increased with increasing phytate consumption, and a phytate consumption higher than 307 mg/day was associated with a normal BMD (t-score > -1). These data suggest that phytate may have a protective effect in bone decalcification by adsorbing on the surfaces of HAP, and a daily consumption of phytate-rich foods (at least one serving/day of legumes or nuts) may help to prevent or minimize bone-loss disorders, such as osteoporosis. However, further studies are needed to gain a better understanding about the mechanism of inhibition of phytate in bone-related diseases (see graphical abstract).

Role of Vitamin K in CKD: Is Its Supplementation Advisable in CKD Patients?

BACKGROUND: Patients with CKD are at an increased risk of developing vascular calcification (VC) and bone complications which translate into a higher morbidity and mortality. The dephosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP) is considered to be an indicator of vitamin K2 status and correlates with markers of VC. It is activated by γ-glutamyl carboxylase that converts inactive MGP into an active form, and vitamin K2 is a cofactor of this reaction. The active form of MGP is a known inhibitor of arterial wall calcification and plays an important role in bone turnover. Recent studies show poor vitamin K2 status in CKD patients. We aimed to review the literature for the association between vitamin K2 status and calcification and bone disease risk and the efficacy of vitamin K2 supplementation in CKD population. SUMMARY: Most CKD patients, including those on renal replacement therapy, have vitamin K2 deficiency. The dp-ucMGP level, a marker of vitamin K2 status, is decreased by vitamin K2 supplementation in CKD patients, but there is no unequivocal proof that it influences arterial calcification progression and bone complications. Key Messages: CKD population are at risk of vitamin K deficiency. Supplementation of vitamin K2 is safe and improves the serum markers of its deficiency. There is lack of strong evidence that vitamin K2 supplementation slows progression of calcification or reduces the frequency of bone complications. More prospective studies are needed.

A possible way to prevent the progression of bone lesions in multiple myeloma via Src-homology-region-2-domain-containing-phosphatase-1 activation.

On the basis of our recent findings, in which multiple receptor-mediated mast cell functions are regulated via a common signaling cascade, we posit that the formation and functioning of osteoclasts are also controlled by a similar common mechanism. These cells are derived from the same granulocyte/monocyte progenitors and share multiple receptors except those that are cell-specific. In both types of cells, all known receptors reside in lipid rafts, form multiprotein complexes with recruited signaling molecules, and are internalized upon receptor engagement. Signal transduction proceeds in a chain of protein phosphorylations, where adaptor protein LAT (linker-for-activation-of-T-cells) plays a central role. The key kinase that associates LAT phosphorylation and lipid raft internalization is Syk (spleen-tyrosine-kinase) and/or an Src-family-kinase, most probably Lck (lymphocyte-specific-protein-tyrosine-kinase). Dephosphorylation of phosphorylated Syk and Lck by activated SHP-1 (Src-homology-region-2-domain-containing-phosphatase-1) terminates the signal transduction and endocytosis of receptors, resulting in inhibition of osteoclast differentiation and other functions. In malignant plasma cells (MM cells) too, SHP-1 plays a similar indispensable role in controlling signal transduction required for survival and proliferation, though BLNK (B-cell-linker-protein), a functional equivalent of LAT and SLP-76 (SH2-domain-containing-leukocyte-protein-of-76-kDa) in B cells, is used instead of LAT. In both osteoclasts and MM cells, therefore, activated SHP-1 acts negatively in receptor-mediated cellular functions. In osteoblasts, however, activated SHP-1 promotes differentiation, osteocalcin generation, and mineralization by preventing both downregulation of transcription factors, such as Ostrix and Runx2, and degradation of ß-catenin required for activation of the transcription factors. SHP-1 is activated by tyrosine phosphorylation and micromolar doses (M-dose) of CCRI-ligand-induced SHP-1 activation. Small molecular compounds, such as A770041, Sorafenib, Nitedanib, and Dovitinib, relieve the autoinhibitory conformation. Activation of SHP-1 by M-dose CCRI ligands or the compounds described may prevent the progression of bone lesions in MM.

Prevention of Bone Destruction by Mechanical Loading Is Not Enhanced by the Bruton's Tyrosine Kinase Inhibitor CC-292 in Myeloma Bone Disease.

Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton's tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.

Rspo1-LGR4 axis in BMSCs protects bone against radiation-induced injury through the mTOR-dependent autophagy pathway.

While mesenchymal stem cells (MSCs) have been widely used to repair radiation-induced bone damage, the molecular mechanism underlying the effects of MSCs in the maintenance of bone homeostasis under radiation stress remains largely unknown. In this study, the role and mechanisms of R-spondin 1 (Rspo1)-leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis on the initiation of self-defense of bone mesenchymal stem cells (BMSCs) and maintenance of bone homeostasis under radiation stress were investigated. Interestingly, radiation increased levels of Rspo1 and LGR4 in BMSCs. siRNA knockdown of Rspo1 or LGR4 aggravated radiation-induced impairment of self-renewal ability and osteogenic differentiation potential of BMSCs. However, exogenous Rspo1 significantly attenuated radiation-induced depletion of BMSCs, and promoted the lineage shift towards osteoblasts. This alteration was associated with the reversal of mammalian target of rapamycin (mTOR) activation and autophagy decrement. Pharmacological and genetic blockade of autophagy attenuated the radio-protective effects of Rspo1, rendering BMSCs more vulnerable to radiation-induced injury. Then bone radiation injury was induced in C57BL6J mice to further determine the radio-protective effects of Rspo1. In mice, administration of Rspo1 recombinant protein alleviated radiation-induced bone loss. Our results uncover that Rspo1-LGR4-mTOR-autophagy axis are key mechanisms by which BMSCs initiate self-defense against radiation and maintain bone homeostasis. Targeting Rspo1-LGR4 may provide a novel strategy for the intervention of radiation-induced bone damage.

Promoting bone health in children and adolescents following solid organ transplantation.

Solid organ transplantation in children and adolescents provides many benefits through improving critical organ function, including better growth, development, cardiovascular status, and quality of life. Unfortunately, bone status may be adversely affected even when overall status is improving, due to issues with pre-existing bone disease as well as medications and nutritional challenges inherent post-transplantation. For all children and adolescents, bone status entering adulthood is a critical determinant of bone health through adulthood. The overall health and bone status of transplant recipients benefits from attention to regular physical activity, good nutrition, adequate calcium, phosphorous, magnesium and vitamin D intake and avoidance/minimization of soda, extra sodium, and obesity. Many immunosuppressive agents, especially glucocorticoids, can adversely affect bone function and development. Minimizing exposure to "bone-toxic" medications is an important part of promoting bone health in children post-transplantation. Existing guidelines detail how regular monitoring of bone status and biochemical markers can help detect bone abnormalities early and facilitate valuable bone-directed interventions. Attention to calcium and vitamin D supplementation, as well as tapering and withdrawing glucocorticoids as early as possible after transplant, can provide best bone outcomes for these children. Dual-energy X-ray absorptiometry can be useful to detect abnormal bone mass and fracture risk in this population and newer bone assessment methods are being evaluated in children at risk for poor bone outcomes. Newer bone therapies being explored in adults with transplants, particularly bisphosphonates and the RANKL inhibitor denosumab, may offer promise for children with low bone mass post-transplantation.

Effects of oleuropein on tumor cell growth and bone remodelling: Potential clinical implications for the prevention and treatment of malignant bone diseases.

Oleuropein (Ole) is the main bioactive phenolic compound present in olive leaves, fruits and olive oil. This molecule has been shown to exert beneficial effects on several human pathological conditions. In particular, recent preclinical and observational studies have provided evidence that Ole exhibits chemo-preventive effects on different types of human tumors. Studies undertaken to elucidate the specific mechanisms underlying these effects have shown that this molecule may thwart several key steps of malignant progression, including tumor cell proliferation, survival, angiogenesis, invasion and metastasis, by modulating the expression and activity of several growth factors, cytokines, adhesion molecules and enzymes involved in these processes. Interestingly, experimental observations have highlighted the fact that most of these signalling molecules also appear to be actively involved in the homing and growth of disseminating cancer cells in bones and, ultimately, in the development of metastatic bone diseases. These findings, and the experimental and clinical data reporting the preventive activity of Ole on various pathological conditions associated with a bone loss, are indicative of a potential therapeutic role of this molecule in the prevention and treatment of cancer-related bone diseases. This paper provides a current overview regarding the molecular mechanisms and the experimental findings underpinning a possible clinical role of Ole in the prevention and development of cancer-related bone diseases.

Effectiveness of Medical Nutrition Therapy to Improve Dietary Habits for Promoting Bone Health in People Living with Chronic HIV.

INTRODUCTION: Previous studies have established the risk of bone loss among people living with HIV affected by antiretroviral therapy drug side effects and inadequate nutrient intake. Until recently, there have been limits on using the medical nutrition therapy (MNT) to improve dietary habits for promoting bone health among people living with HIV. This was a randomized controlled trial study aimed to investigate the effectiveness of MNT in improving the bone health in people living with HIV by promoting dietary habits. METHODS: PLHIV at Queen Savang Vadhana Memorial Hospital were randomly grouped (by quota sampling) into the MNT group (intervention group) and the control group. One hundred and thirty PLHIV were recruited to participate in this study by convenient sampling. Sixty-five participants of the MNT group made a total of 6 appointments (for 12 weeks) to meet registered dietitians for receiving MNT to improve dietary habits for improving bone health, while 65 participants in the control group received only routine care at the hospital service center. RESULTS: In general, participants in the MNT group had significant increase in the amounts of calcium, vitamin D, potassium, and phosphorus intakes and length of exercise after the final week compared with before intervention. Also, they had significantly higher amount of nutrient intakes (calcium, vitamin D, potassium, and phosphorus) and length of exercise than the control group after finishing the final week of the experiment. CONCLUSION: In conclusion, MNT is effective for improving food habits and physical activity to promote bone health among people living with HIV.

An intelligent vancomycin release system for preventing surgical site infections of bone tissues.

Preventing surgical site infections (SSIs) of implants has drawn significant attention in both basic and clinical research. Implants with convenient preparation methods and intelligent drug release capabilities are highly needed to resist bacterial infection. Herein, we designed an intelligent drug-release system, which can be instantly incorporated with implants during the surgical process. The drug-release system involves ß-glycerophosphate (ß-GP) and chitosan (CS) as a thermosensitive hydrogel for instant construction onto implants and hyaluronic acid (HA) as a trigger to release vancomycin hydrochloride (VH) on demand. Tertiary calcium phosphate (TCP) scaffolds (implants) are vacuum-adsorbed in a solution of the intelligent vancomycin-release system (VH-HA-CS/ß-GP), followed by heating for 40 min at 80 °C to form VH-HA-CS/ß-GP@TCP. The drug-release hydrogel intelligently releases vancomycin depending on the concentration of hyaluronidase, which is secreted by Staphylococcus aureus (S. aureus) in infection sites. Furthermore, VH-HA-CS/ß-GP@TCP showed effective antibacterial properties in vitro and in vivo. The VH-HA-CS/ß-GP drug-release system can be conveniently prepared during surgery for intelligently preventing SSIs in bone tissue.