Bone Physiology Research Articles

A crosstalk between 'osteocyte lacunal-canalicular system' and metabolism.

Considering the importance, bone physiology has long been studied to understand what systematic and cellular impact its cells and functions have. Exploring more questions is a substantially solid way to improve the understanding of bone physiological functions in/out sides. In adult bone, osteocytes (Ots) form about 95% of bone cells and live the longest lifespan inside their mineralized surroundings. Ots are the endocrine cells and originate from blood vessel's endothelial cells. In this work, we discussed the vital role of the "Ots". To determine the association between osteocytes' network with metabolic parameters in healthy mice, the experiments were performed on ten (10) adult C57BL6 male mice. Fasting blood and bone samples were collected weekly from mice for measurement of metabolic parameters and bone morphology. Scanning electron microscopy (SEM) revealed a 2D fine morphology of the bone which indicates a strong functional interconnection with bone nano/micro, and macro components of the organs. The long-branched canaliculi look like neurocytes in structure. The morphology and quantitative measurements of the osteocyte lacunal-canalicular system showed its wide spectrum spatial resolution of the positive and negative relationship within this system or metabolite parameters, confirming a strong cross connection between osteocyte lacunal-canalicular system and metabolism. We believe that the findings of this study can deliver a strategy about the potential roles of metabolic relation among osteocytes, insulin, and lipid in management of bone and metabolic diseases.

CORROSION PREDICTION OFMAGNESIUM IMPLANT USING MULTISCALE MODELING BASED ON MACHINE LEARNING ALGORITHMS

Significant thoughtful research is really necessary to improve the patient outcomes and reduce the social and financial burdens associated with implant failure. The primary focus of the researchers is to minimize the major implant failure due to corrosion attributed to making orthopedic surgery safer and more effective. Hence, a critical review has been done in this present article on the various multiscale modelings based on machine learning algorithms (MLAs) to predict the corrosion behavior of magnesium (Mg) alloy implants. According to the best of the authors' knowledge, all the available multiscale modelings tools, such as artificial neural network (ANN), least absolute shrinkage and selection operator (LASSO) regression model, multiple linear regression and random forest regression (RFR) models, etc., are methodically presented and discussed in detailed here for the prediction of corrosion mechanism. Subsequently, various multiscale model tools and assessment metrics for models have been thoroughly compared and criticized for better understanding and optimizing of the corrosion behavior of implants. The comparison indicates that the RFR model may be the best option, whereas the LASSO regression model and ANNs show inefficient performance for the prediction of corrosion behavior. Apart from the multiscale modeling approach, the authors have also explored the physiology and properties of alloys, bone implant, immune and tissue system, and the corrosion control mechanisms of Mg alloy. Finally, the present review on multiscale modeling approach and assessment metrics models will enhance the knowledge and understanding of the corrosion behavior of Mg alloy for implant application.

Investigating mechanical and inflammatory pathological mechanisms in osteoarthritis using MSC-derived osteocyte-like cells in 3D.

Changes to bone physiology play a central role in the development of osteoarthritis with the mechanosensing osteocyte releasing factors that drive disease progression. This study developed a humanised in vitro model to detect osteocyte responses to either interleukin-6, a driver of degeneration and bone remodelling in animal and human joint injury, or mechanical loading, to mimic osteoarthritis stimuli in joints. Human MSC cells (Y201) were differentiated in 3-dimensional type I collagen gels in osteogenic media and osteocyte phenotype assessed by RTqPCR and immunostaining. Gels were subjected to a single pathophysiological load or stimulated with interleukin-6 with unloaded or unstimulated cells as controls. RNA was extracted 1-hour post-load and assessed by RNAseq. Markers of pain, bone remodelling, and inflammation were quantified by RT-qPCR and ELISA. Y201 cells embedded within 3D collagen gels assumed dendritic morphology and expressed mature osteocytes markers. Mechanical loading of the osteocyte model regulated 7564 genes (Padj p<0.05, 3026 down, 4538 up). 93% of the osteocyte transcriptome signature was expressed in the model with 38% of these genes mechanically regulated. Mechanically loaded osteocytes regulated 26% of gene ontology pathways linked to OA pain, 40% reflecting bone remodelling and 27% representing inflammation. Load regulated genes associated with osteopetrosis, osteoporosis and osteoarthritis. 42% of effector genes in a genome-wide association study meta-analysis were mechanically regulated by osteocytes with 10 genes representing potential druggable targets. Interleukin-6 stimulation of osteocytes at concentrations reported in human synovial fluids from patients with OA or following knee injury, regulated similar readouts to mechanical loading including markers of pain, bone remodelling, and inflammation. We have developed a reproducible model of human osteocyte like cells that express >90% of the genes in the osteocyte transcriptome signature. Mechanical loading and inflammatory stimulation regulated genes and proteins implicated in osteoarthritis symptoms of pain as well as inflammation and degeneration underlying disease progression. Nearly half of the genes classified as 'effectors' in GWAS were mechanically regulated in this model. This model will be useful in identifying new mechanisms underlying bone and joint pathologies and testing drugs targeting those mechanisms.

РОЛЬ ЧАСТОТНО- РЕЗОНАНСНОГО АНАЛИЗА В ИССЛЕДОВАНИИ ДЕНТАЛЬНЫХ ИМПЛАНТАТОВ, УСТАНОВЛЕННЫХ В РЕКОНСТРУИРОВАННЫЕ АЛЬВЕОЛЯРНЫЕ ОТРОСТКИ С НЕБОЛЬШИМ ОБЪЕМОМ КОСТИ ЧЕЛЮСТЕЙ

The use of dental implants being the intraosseous artificial fixtures is often required for orthopedic rehabilitation of completely edentulous patients; for their placement, adequate amount of bone tissue is needed, which in many cases is insufficient due to physiological bone loss, long-term wearing of full dentures, the duration of edentulism and complex clinical situations caused by maxillofacial injuries or general somatic diseases. Implant placement in the above situations requires timely preparation of deficient alveolar ridge by means of osteoplastic surgery. In its turn, the newly formed regenerated bone by its histological, physicomechanical and structural-functional properties can only approach the recipient bone tissue; therefore, the issue of implant osseointegration and its functional loading in regenerated bone remains debatable. This research uses the method of frequency-resonance analysis showing implant stability coefficient numerically equal to the ISQ (Implant stability Quotient) values and reflecting the percentage of the osseointegration area of the intraosseous part of the implant. The results of research obtained by means of frequency-resonance analysis have proved that with the timely start of implant usage and adequate functional loading, ISQ values increase, that is, increases the osseointegration area along the interface of the intraosseous part of the implant placed in regenerated bone. Comparative results of research reflecting ISQ values in 12 months after implant placement in bone augmented using various forms of autogenous bonegrafts, have been presented; therefore, a conclusion can be made that there is a direct relationship between osseointegration under conditions of functional chewing load and the shape and size of autogenous bonegrafts.

An Update on Hypomagnesemia and Hypermagnesemia

Magnesium is an essential element with a pleiotropic role in human biology. Despite tight intestinal and renal regulation of its balance, insufficient intake can finally result in hypomagnesemia, which is a proxy of intracellular deficiency. Conditions such as diabetes, cancer, and infections are often associated with hypomagnesemia, which mostly predicts an unfavorable outcome. The effects of hypomagnesemia can either be direct and include neurological and cardiovascular symptoms or indirect, taking a mechanistic role in inflammation, endothelial dysfunction, and oxidative stress. The indication for intravenous magnesium as a treatment of torsades de pointes and pre-eclampsia is unrefuted, but new indications of peroral or intravenous supplementation, albeit with less supporting evidence, have emerged suggesting, respectively, an attenuation of vascular calcification in chronic kidney disease and improved rate control in atrial fibrillation. Other potential beneficial properties of magnesium, which were claimed by observational data, such as lipid lowering and renal protection, were not, or only partially, investigated in randomized controlled trials. Thus, the role of peroral supplementation of mild chronic asymptomatic hypomagnesemia should be separated from the more targeted prescription of magnesium in specific study populations. (Severe) hypermagnesemia is potentially life-threatening and occurs almost uniformly in subjects with severe renal failure exposed to either supplements or to magnesium-containing cathartics or antacids. Moderate hypermagnesemia is very common in pre-eclamptic women treated with intravenous magnesium. For most (but not all) studied endpoints, mild hypermagnesemia yields a survival benefit. Long-lasting concerns about the potential negative effects of mild hypermagnesemia on bone physiology and structure have so far not been unequivocally demonstrated to be troublesome.

Osteoporotic Bone Regeneration via Plenished Biomimetic PLGA Scaffold with Sequential Release System.

Achieving satisfactory bone tissue regeneration in osteoporotic patients with ordinary biomaterials is challenging because of the decreased bone mineral density and aberrant bone microenvironment. In addressing this issue, a biomimetic scaffold (PMEH/SP), incorporating 4-hexylresorcinol (4HR), and substance P (SP) into the poly(lactic-go-glycolic acid) (PLGA) scaffold with magnesium hydroxide (M) and extracellular matrix (E) is introduced, enabling the consecutive release of bioactive agents. 4HR and SP induced the phosphorylation of p38 MAPK and ERK in human umbilical vein endothelial cells (HUVECs), thereby upregulating VEGF expression level. The migration and tube-forming ability of endothelial cells can be promoted by the scaffold, which accelerates the formation and maturation of the bone. Moreover, 4HR played a crucial role in the inhibition of osteoclastogenesis by interrupting the IκB/NF-κB signaling pathway and exhibiting SP, thereby enhancing the migration and angiogenesis of HUVECs. Based on such a synergistic effect, osteoporosis can be suppressed, and bone regeneration can be achieved by inhibiting the RANKL pathway in vitro and in vivo, which is a commonly known mechanism of bone physiology. Therefore, the study presents a promising approach for developing a multifunctional regenerative material for sophisticated osteoporotic bone regeneration.

Advantages and Limitations of Diabetic Bone Healing in Mouse Models: A Narrative Review.

Diabetes represents a major risk factor for impaired fracture healing. Type 2 diabetes mellitus is a growing epidemic worldwide, hence an increase in diabetes-related complications in fracture healing can be expected. However, the underlying mechanisms are not yet completely understood. Different mouse models are used in preclinical trauma research for fracture healing under diabetic conditions. The present review elucidates and evaluates the characteristics of state-of-the-art murine diabetic fracture healing models. Three major categories of murine models were identified: Streptozotocin-induced diabetes models, diet-induced diabetes models, and transgenic diabetes models. They all have specific advantages and limitations and affect bone physiology and fracture healing differently. The studies differed widely in their diabetic and fracture healing models and the chosen models were evaluated and discussed, raising concerns in the comparability of the current literature. Researchers should be aware of the presented advantages and limitations when choosing a murine diabetes model. Given the rapid increase in type II diabetics worldwide, our review found that there are a lack of models that sufficiently mimic the development of type II diabetes in adult patients over the years. We suggest that a model with a high-fat diet that accounts for 60% of the daily calorie intake over a period of at least 12 weeks provides the most accurate representation.

Efikasiteti i aplikimit të plazmës të pasuruar me trombocite (PRP) si graft autolog në procedurën kirurgjikale për ngritjen e fundit të sinusit maksilar për vendosjen e implanteve dentare

Placement of dental implants in the upper jaw can pose difficulties due to insufficient bone volume caused by si- nus pneumatization and physiological bone resorption. The aim of this study was to evaluate the impact of using autologous platelet-rich plasma as a graft material for si- nus lift procedures. The mean height of the alveolar bone between the floor of the maxillary sinus and the alveolar crest was 2.50 ± 0.73 mm preoperatively, 16.90 ± 1.93 mm post-surgical procedure, and 14.4 mm after 6 months (p &lt; 0.05). There were statistically significant differences in the changes of the values of the most mesial and distal distances in the augmented region. The average dimen- sions of the placed dental implants were 10 mm in length and 3.98 mm in diameter, with 88% high primary stabili- ty in the placed implants and 100% implant survival after a 6-month period. The application of platelet-rich plasma in maxillary sinus floor elevation procedures yields good results in terms of new bone formation, implant osseointe- gration, and positive clinical outcomes. However, further research is needed over a longer time interval to better understand the role and potential of this autogenous graft material in regenerative dentistry.

Importance of Metalloproteinase Enzyme Group in Selected Skeletal System Diseases.

Bone tissue is a dynamic structure that is involved in maintaining the homeostasis of the body due to its multidirectional functions, such as its protective, endocrine, or immunological role. Specialized cells and the extracellular matrix (ECM) are responsible for the remodeling of specific bone structures, which alters the biomechanical properties of the tissue. Imbalances in bone-forming elements lead to the formation and progression of bone diseases. The most important family of enzymes responsible for bone ECM remodeling are matrix metalloproteinases (MMPs)-enzymes physiologically present in the body's tissues and cells. The activity of MMPs is maintained in a state of balance; disruption of their activity is associated with the progression of many groups of diseases, including those of the skeletal system. This review summarizes the current understanding of the role of MMPs in bone physiology and the pathophysiology of bone tissue and describes their role in specific skeletal disorders. Additionally, this work collects data on the potential of MMPs as bio-markers for specific skeletal diseases.

EFFECTS OF RECOMBINED HUMAN BONE MORPHOGENETIC PROTEIN-2 AS ALVEOLAR RIDGE PRESERVATION ON PAIN REDUCTION AND SOFT TISSUE HEALING PROCESS: A SPLIT MOUTH DESIGNED PILOT STUDY

Background: The alveolar ridge undergoes physiological bone resorption following tooth extraction. Several alveolar ridge preservation (ARP) techniques have been researched and developed in an effort to reduce this process and maintain a favorable volume and morphology of the alveolar ridge for appropriate implant placement. Bone morphogenetic proteins (BMPs) are proteins derived from a subgroup of the transforming growth factor  family that accelerates ossification by controlling essential factors of the bone induction cascade, resulting in the proliferation of osteoblasts from mesenchymal stem cells and the biosynthesis of bone matrices. One of these BMPs is recombinant human bone morphogenetic protein-2 (rhBMP-2) that has been authorized to be used for ARP. Objective: This study aims to evaluate the effect of rhBMP-2 on the healing process and the level of pain following dental extraction. Methods: In this split-mouth pilot study, 11 patients underwent extractions of a minimum of two teeth, and randomly, one of the alveolar sockets was filled with a hemostatic sponge while the other was filled with a hemostatic sponge embedded with rhBMP-2. Both sockets were sutured using the X technique. Wound healing measurements were done on days 3, 7, and 14, and each participant was requested to document his pain experience using the Numerical Rating Scale (NRS). Results: In accordance with clinical evidence, it was observed that the mean pain score was at its peak on day 0 and progressively diminished in the subsequent days. Notably, this decline was more pronounced in the rhBMP-2 group compared to the control group. Importantly, a statistically significant reduction in pain level was detected on day 3 within the rhBMP-2 group, in contrast to the control group (P-value &lt; 0.05). This indicated that the application of rhBMP-2 led to a noteworthy and meaningful alleviation of pain on the third day after treatment, surpassing the impact observed in the control group. For the wound healing changes, it uncovered statistically significant mean differences across various time intervals: day 0 and day 3, day 0 and day 7, day 0 and day 14, day 3 and day 7, and day 7 and day 14 (P-value &lt; 0.0001). These significant differences strongly suggest dynamic changes in wound closure rates over time. Furthermore, the observed differences were more pronounced in the rhBMP-2-treated group compared to the control group. This augmentation of differences indicates that the utilization of rhBMP-2 for ARP within a fresh socket site resulted in a heightened acceleration of the wound healing process. Conclusion: Our results suggest that rhBMP-2 can decrease post-operative pain after tooth extraction and accelerate the soft tissue healing process.

Homeostatic Regulation of Pro-Angiogenic and Anti-Angiogenic Proteins via Hedgehog, Notch Grid, and Ephrin Signaling in Tibial Dyschondroplasia.

Precise coupling of two fundamental mechanisms, chondrogenesis and osteogenesis via angiogenesis, plays a crucial role during rapid proliferation of growth plates, and alteration in their balance might lead to pathogenic conditions. Tibial dyschondroplasia (TD) is characterized by an avascular, non-mineralized, jade-white "cartilaginous wedge" with impaired endochondral ossification and chondrocyte proliferation at the proximal end of a tibial bone in rapidly growing poultry birds. Developing vascular structures are dynamic with cartilage growth and are regulated through homeostatic balance among pro and anti-angiogenic proteins and cytokines. Pro-angiogenic factors involves a wide spectrum of multifactorial mitogens, such as vascular endothelial growth factors (VEGF), platelet-derived growth factors (PDGF), basic fibroblast growth factor (bFGF), placental growth factors, transforming growth factor-β (TGF-β), and TNF-α. Considering their regulatory role via the sonic hedgehog, notch-gridlock, and ephrin-B2/EphB4 pathways and inhibition through anti-angiogenic proteins like angiostatin, endostatin, decoy receptors, vasoinhibin, thrombospondin, PEX, and troponin, their possible role in persisting inflammatory conditions like TD was studied in the current literature review. Balanced apoptosis and angiogenesis are vital for physiological bone growth. Any homeostatic imbalance among apoptotic, angiogenetic, pro-angiogenic, or anti-angiogenic proteins ultimately leads to pathological bone conditions like TD and osteoarthritis. The current review might substantiate solid grounds for developing innovative therapeutics for diseases governed by the disproportion of angiogenesis and anti-angiogenesis proteins.

Skeletal Effects of Soy Isoflavone in Humans: Bone Mineral Density and Bone Markers

The potential skeletal effects of soy isoflavones in humans have garnered significant interest owing to their structural resemblance to endogenous estrogen and their potential to impact bone health. This abstract provides a concise overview of the current understanding of the effects of soy isoflavones on bone mineral density (BMD) and bone markers. Numerous studies have investigated the relationship between soy isoflavone consumption and BMD. Some studies have suggested a positive association between soy isoflavone intake and BMD, particularly among postmenopausal women. Isoflavones may exert their effects through estrogen receptor-mediated pathways, potentially mitigating bone loss by reducing osteoclastic activity and promoting osteoblastic functions. However, conflicting results have been reported, with certain studies demonstrating no significant impact on BMD. In addition to BMD, bone markers such as serum osteocalcin, urinary deoxypyridinoline, and tartrate-resistant acid phosphatase have been evaluated to elucidate the mechanistic effects of soy isoflavones on bone metabolism. These markers provide insights into bone turnover, resorption, and formation. Clinical trials have reported mixed findings regarding the influence of soy isoflavones on bone markers, reflecting the complexity of their interaction with bone physiology

Bone regeneration in critical-size defects of the mandible using biomechanically adapted CAD/CAM hybrid scaffolds: An in vivo study in miniature pigs

The study aimed to analyze bone regeneration in critical-size defects using hybrid scaffolds biomechanically adapted to the specific defect and adding the growth factor rhBMP-2.For this animal study, ten minipigs underwent bilateral defects in the corpus mandibulae and were subsequently treated with novel cylindrical hybrid scaffolds. These scaffolds were designed digitally to suit the biomechanical requirements of the mandibular defect, utilizing finite element analysis. The scaffolds comprised zirconium dioxide-tricalcium phosphate (ZrO2-TCP) support struts and TCP foam ceramics. One scaffold in each animal was loaded with rhBMP-2 (100 μg/cm³), while the other served as an unloaded negative control. Fluorescent dyes were administered every 2 weeks, and computed tomography (CT) scans were conducted every 4 weeks. Euthanasia was performed after 3 months, and samples were collected for examination using micro-CT and histological evaluation of both hard and soft tissue.Intravital CT examinations revealed minor changes in radiographic density from 4 to 12 weeks postoperatively. In the group treated with rhBMP-2, radiographic density shifted from 2513 ± 128 (mean ± SD) to 2606 ± 115 Hounsfield units (HU), while the group without rhBMP-2 showed a change from 2430 ± 131 to 2601 ± 67 HU. Prior to implantation, the radiological density of samples measured 1508 ± 30 mg HA/cm³, whereas post-mortem densities were 1346 ± 71 mg HA/cm³ in the rhBMP-2 group and 1282 ± 91 mg HA/cm³ in the control group (p = 0.045), as indicated by micro-CT measurements. The histological assessment demonstrated successful ossification in all specimens. The newly formed bone area proportion was significantly greater in the rhBMP-2 group (48 ± 10%) compared with the control group without rhBMP-2 (42 ± 9%, p = 0.03). The mean area proportion of remaining TCP foam was 23 ± 8% with rhBMP-2 and 24 ± 10% without rhBMP-2.Successful bone regeneration was accomplished by implanting hybrid scaffolds into critical-size mandibular defects. Loading these scaffolds with rhBMP-2 led to enhanced bone regeneration and a uniform distribution of new bone formation within the hybrid scaffolds. Further studies are required to determine the adaptability of hybrid scaffolds for larger and potentially segmental defects in the maxillofacial region.

Imaging Evaluation of Platelet-Rich Fibrin in Post-Exodontic Bone Regeneration: A Systematic Review.

Tooth extraction is the most common procedure in dental practice. However, in the long term, it may cause alveolar ridge atrophy. This systematic review aimed to evaluate the role of platelet-rich fibrin (PRF) in post-exodontic alveolar ridge preservation in terms of its effectiveness in the regeneration of bone tissue as assessed by imaging and its efficacy compared to physiological bone healing. The study is presented in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. This systematic review was conducted using electronic databases such as PubMed, Scopus, Web of Science, and Science Direct. The gray literature search was conducted in the New York Academy of Medicine Grey Literature Report. All the studies in this systematic review were randomized controlled trials (RCTs). The risk of bias was performed according to the Cochrane Handbook for Systematic Reviews of Interventions 6.2 (RevMan 6.2). Considering the inclusion and exclusion criteria, we included 17 randomized clinical trials published up to 2022 investigating the efficacy of PRF in post-exodontic bone regeneration. Based on the results of clinical studies, it can be stated that despite not being statistically significant, PRF promotes neoformation and prevents bone loss between three and four months post-extraction.

Osteoblast-lineage calcium/calmodulin-dependent kinase 2 delta and gamma regulates bone mass and quality.

Bone regulates its mass and quality in response to diverse mechanical, hormonal, and local signals. The bone anabolic or catabolic responses to these signals are often received by osteocytes, which then coordinate the activity of osteoblasts and osteoclasts on bone surfaces. We previously established that calcium/calmodulin-dependent kinase 2 (CaMKII) is required for osteocytes to respond to some bone anabolic cues in vitro. However, a role for CaMKII in bone physiology in vivo is largely undescribed. Here, we show that conditional codeletion of the most abundant isoforms of CaMKII (delta and gamma) in mature osteoblasts and osteocytes [Ocn-cre:Camk2d/Camk2g double-knockout (dCKO)] caused severe osteopenia in both cortical and trabecular compartments by 8 wk of age. In addition to having less bone mass, dCKO bones are of worse quality, with significant deficits in mechanical properties, and a propensity to fracture. This striking skeletal phenotype is multifactorial, including diminished osteoblast activity, increased osteoclast activity, and altered phosphate homeostasis both systemically and locally. These dCKO mice exhibited decreased circulating phosphate (hypophosphatemia) and increased expression of the phosphate-regulating hormone fibroblast growth factor 23. Additionally, dCKO mice expressed less bone-derived tissue nonspecific alkaline phosphatase protein than control mice. Consistent with altered phosphate homeostasis, we observed that dCKO bones were hypo-mineralized with prominent osteoid seams, analogous to the phenotypes of mice with hypophosphatemia. Altogether, these data reveal a fundamental role for osteocyte CaMKIIδ and CaMKIIγ in the maintenance of bone mass and bone quality and link osteoblast/osteocyte CaMKII to phosphate homeostasis.

Dietary restriction inhibits bone formation in alveolar bone modeling and remodelling

Objective: Methods: Balb/C mice weaned at the age of 21 days were assigned to one of the following groups: control group fed a regular hard diet ad libitum (food consumption was measured daily), and dietary restricted group (DR) received 75% of the amount of food consumed by the respective control mice the previous day. Body weight of all animals was recorded throughout. Mice were euthanized in groups of ten at 25 and 60 days of experience. Mandibles were dissected, descalcified in EDTA and embedded in paraffin. Buccolingual sections of the mesial root of the first lower molar were stained with hematoxylin-eosin and submitted to histomorphometric studies. Results: At 25 days, DR mice shows bone formation values lower than control animals for modeling and remodeling sides, coupled to an increase with bone at rest values in the modeling side. At 60 days, DR mice shows bone formation values lower than control animals in the modeling side linked with a similar increase in values corresponding to bone resorption and bone at rest. In the remodeling side, no differences in bone formation were observed between control and DR mice. However, high bone resorption and a decrease in bone at rest areas were observed. Conclusions: Dietery restriction impaires bone formation in physiologic alveolar bone modeling and remodeling.

PIVKA‑II is associated with liver function, bone metabolism, and muscle function in patients with liver disease.

Protein induced by vitamin K (VK) absence-II (PIVKA-II) is a sensitive marker for diagnosing hepatoma but is occasionally detected in patients without hepatoma Here, the clinical significance of serum PIVKA-II levels in patients who were not administered warfarin and did not have hepatoma or liver disease were evaluated. As VK is related to muscle and bone metabolism, PIVKA-II and clinical factors related to bone and muscle were compared. A total of 441 patients with various liver diseases were evaluated. Of these, 236 patients were female. Clinical factors and anthropometric measurements were obtained for each participant during outpatient visits. Among the clinical factors, type I procollagen N-propeptide (P1NP), a low titer of undercarboxylated osteocalcin (ucOC), and 25(OH) vitamin D (VD) were used as bone metabolic markers, and SARC-F and grip strength were used as muscle-related markers. Serum PIVKA-II levels above the upper limit were associated with Child B/C (Child-Pugh score), high titers of total P1NP, and low titers of ucOC in females, and alcohol-related liver disease and low VD in males. The titer of PIVKA-II were associated with immunoglobulin (Ig) A and prothrombin time (PT)-international normalized ratio (INR) in females, and fibrosis-4-4, IgG, total bilirubin, PT-INR, and SARC-F in males. Elevated PIVKA-II levels were associated with abnormal bone physiology in females, weak muscles in males, and severe liver disease in both sexes. Assessing PIVKA-II may assist in evaluating the clinical and bone-muscle metabolic stages in liver disease. Nutrition and supplementation with fat-soluble vitamins, including VK and VD may thus serve as a potential method to alleviate or prevent bone-muscle pathophysiology in patients with liver disease.

Human Wharton’s jelly-derived mesenchymal stromal cells promote bone formation in immunodeficient mice when administered into a bone microenvironment

BackgroundWharton’s Jelly (WJ) Mesenchymal Stromal Cells (MSC) have emerged as an attractive allogeneic therapy for a number of indications, except for bone-related conditions requiring new tissue formation. This may be explained by the apparent recalcitrance of MSC,WJ to differentiate into the osteogenic lineage in vitro, as opposed to permissive bone marrow (BM)-derived MSCs (MSC,BM) that readily commit to bone cells. Consequently, the actual osteogenic in vivo capacity of MSC,WJ is under discussion.MethodsWe investigated how physiological bone environments affect the osteogenic commitment of recalcitrant MSCs in vitro and in vivo. To this end, MSC of BM and WJ origin were co-cultured and induced for synchronous osteogenic differentiation in vitro using transwells. For in vivo experiments, immunodeficient mice were injected intratibially with a single dose of human MSC and bone formation was evaluated after six weeks.ResultsCo-culture of MSC,BM and MSC,WJ resulted in efficient osteogenesis in both cell types after three weeks. However, MSC,WJ failed to commit to bone cells in the absence of MSC,BM’s osteogenic stimuli. In vivo studies showed successful bone formation within the medullar cavity of tibias in 62.5% of mice treated with MSC, WJ. By contrast, new formed trabeculae were only observed in 25% of MSC,BM-treated mice. Immunohistochemical staining of human COXIV revealed the persistence of the infused cells at the site of injection. Additionally, cells of human origin were also identified in the brain, heart, spleen, kidney and gonads in some animals treated with engineered MSC,WJ (eMSC,WJ). Importantly, no macroscopic histopathological alterations, ectopic bone formation or any other adverse events were detected in MSC-treated mice.ConclusionsOur findings demonstrate that in physiological bone microenvironment, osteogenic commitment of MSC,WJ is comparable to that of MSC,BM, and support the use of off-the-shelf allogeneic MSC,WJ products in bone repair and bone regeneration applications.

Circ_ST6GAL1-mediated competing endogenous RNA network regulates TGF-β1-stimulated matrix Metalloproteinase-13 expression via Runx2 acetylation in osteoblasts

Transforming growth factor-beta1 (TGF-β1) stimulates matrix metalloproteinase-13 (MMP-13, a bone-remodeling gene) expression, and this effect requires p300-mediated Runx2 (Runt-related transcription factor 2) acetylation in osteoblasts. p300 and Runx2 are transcriptional coactivator and bone transcription factor, respectively, which play key roles in the regulation of bone-remodeling genes. Non-coding ribonucleic acids (ncRNAs), such as long ncRNAs (lncRNAs) and microRNAs (miRNAs), have been linked to both physiological and pathological bone states. In this study, we proposed that TGF-β1-mediated stimulation of MMP-13 expression is due to the downregulation of p300 targeting miRNAs in osteoblasts. We identified miR-130b-5p as one of the miRNAs downregulated by TGF-β1 in osteoblasts. Forced expression of miR-130b-5p decreased p300 expression, Runx2 acetylation, and MMP-13 expression in these cells. Furthermore, TGF-β1 upregulated circ_ST6GAL1, (a circular lncRNA) in osteoblasts; circRNA directly targeted miR-130b-5p. Antisense-mediated knockdown of circ_ST6GAL1 restored the function of miR-130b-5p, resulting in downregulation of p300, Runx2, and MMP-13 in these cells. Hence, our results suggest that TGF-β1 influences circ_ST6GAL1 to sponge and degrade miR-130b-5p, thereby promoting p300-mediated Runx2 acetylation for MMP-13 expression in osteoblasts. Thus, the circ_ST6GAL1/miR-130b-5p/p300 axis has potential significance in the treatment of bone and bone-related disorders.

Interleukin-23 receptor gene polymorphisms in osteoporosis

Objectives: Osteoporosis (OP) is a usual disease with a possible genetic predisposition. IL-23 plays a role in physiological bone remodeling and regulates the activity of cells of the bone either directly or indirectly on bone-resorbing osteoclasts as well as on bone-forming osteoblasts. Recent animal and human trials have revealed the main pro-osteoclastogenic activities for the IL-23 pathway. We examined nine single nucleotide polymorphisms (SNPs) in the interleukin-23 receptor (IL-23R) in 100 OP patients and gender- and age-matched 96 healthy volunteers. The most analyzed SNPs in the recent rheumatology literature were selected. Methods: In addition to gene polymorphisms several laboratory parameters (osteocalcin, parathormone, vitamine D) were investigated. Independent Samples t-test and Mann-Whitney-U test were used to compare several demographic and clinical parameters between the groups. P-value &amp;lt; 0.05 was accepted to be statistically significant. Results: Having the heterozygous GA genotype of IL-23R rs1004819 and the heterozygous CT genotype of Il-23R rs7530511 significantly increase the risk of developing OP (adjusted OR: 3.51, p = 0.031 and OR: 2.41, p = 0.027, respectively). The wild homozygous GG genotype of Il-23R rs11209032 had higher osteocalcin levels compared with the mutant homozygous AA genotype (18.75 ± 9.76, p = 0.009). Conclusions: Our findings suggest that several IL-23R gene polymorphisms are seen more often in osteoporosis patients than in healthy volunteers. In addition, some SNPs were related to higher serum osteocalcin levels.