Treatment Of Bone-related Diseases Research Articles

Fluid-solid coupling numerical simulation of entire rat caudal vertebrae under dynamic loading

Trabeculae bone undergoes directional growth along the applied force under physiological loading. The growth of bone structure relies on the coordinated interplay among osteocytes, osteoblasts, and osteoclasts. Under normal circumstances, bone remodeling maintains a state of equilibrium. Excessive bone formation can lead to osteosclerosis, while excessive bone resorption can result in osteoporosis and osteonecrosis. The investigation of the structural characteristics of trabeculae and the mechanotransduction between bone cells plays a vital role in the treatment of bone-related diseases. In this study, a fluid-solid coupling model of the entire vertebral bone was established based on micro-CT images obtained from rat tail vertebrae subjected to tensile loading experiments. The flow characteristics of bone marrow and the mechanical response of osteocytes in different regions under physiological loading were investigated. The results revealed a U-shaped distribution of wall fluid shear stress (FSS) along the longitudinal axis in trabecular bone, with higher FSS regions exhibiting greater mechanical stimulation on osteocytes. These findings elucidate a positive correlation between the mechanical microenvironment among osteocytes, osteoblasts, and osteoclasts, providing potential strategies for the prevention and treatment of bone diseases.

Advances in the Study of Exosomes as Drug Delivery Systems for Bone-Related Diseases.

Bone-related diseases are major problems and heavy burdens faced by modern society. Current clinical approaches for the treatment of these pathological conditions often lead to complications and have limited therapeutic efficacy. In this context, the development of nanotherapeutic platforms, such as extracellular vesicles, can improve the relevant therapeutic effects. In particular, exosomes are nano-sized, lipid bilayer extracellular vesicles secreted by many cells in mammals. Due to their innate capacity to transport materials-including proteins, lipids, and genes-among cells, as well as their innate attraction to target cells, they are considered to be a crucial medium for cell communication and are involved in a number of biological processes. Exosomes have been used as drug delivery vehicles in recent bone tissue engineering studies, in order to regulate bone homeostasis. However, the precise workings of the exosome regulatory network in maintaining bone homeostasis and its potential for treating bone injury remain unclear. To provide a fresh perspective for the study of exosomes in drug delivery and bone-related diseases, in this paper, we review recent studies on the roles of exosomes for drug delivery in bone homeostasis and bone-related diseases, as well as the composition and characteristics of exosomes and their regulatory roles in bone homeostasis and bone-related diseases, aiming to provide new ideas for the therapeutic application of exosomes in the treatment of bone-related diseases.

Peptide modified geniposidic acid targets bone and effectively promotes osteogenesis

sBackgroundGeniposidic acid (GPA), one of the active components of Eucommia ulmoides, promote bone formation and treat osteoporosis by activating farnesoid X receptor (FXR). However, GPA has low oral availability and lack of bone targeting in the treatment of bone related diseases. With the development of modern technology, small molecules, amino acids, or aptamers are used for biological modification of drugs and target cells in bone tissue, which has become the trend of bone targeted research.MethodsIn this study, SDSSD (an osteoblast-targeting peptide) were modified in GPA using Fmoc solid-phase synthesis technique to form a new SDSSD-GPA conjugate (SGPA). The bone targeting of SGPA was evaluated using in vivo imaging and cell co-culture. In vitro, the effect of SGPA on cytotoxicity, osteoblastic activity, and mineralization ability were studied in mouse primary osteoblasts (OBs). In vivo, the therapeutic effect of SGPA on osteoporosis using an ovariectomized (OVX) mouse model. The bone mass, histomorphometry, serum biochemical parameters, and the molecular mechanism were evaluated.ResultsSGPA was enriched in OBs and tends to accumulate in bone tissue. In vitro, SGPA significantly enhanced the osteogenic activity and mineralization of OBs compared with GPA. In vivo, SGPA enhanced serum BALP and P1NP levels, increased the trabecular bone mass of the mice, and SGPA administration have a higher bone mineralization deposition rate than the GPA-treated mice. Moreover, SGPA significantly activated FXR and Runt-related transcription factor 2 (RUNX2).ConclusionsCollectively, SGPA is enriched into OBs, and promotes bone formation by activating FXR-RUNX2 signalling, effectively treating osteoporosis at relatively low doses.The translational potential of this articleThis study demonstrates a more efficient and safe application of GPA in treating osteoporosis, provide a new concept for the bone targeted application of natural compounds.

Latest Research Findings on the Regulation of Bone Homeostasis by ALK3

Bone remodeling, which is well orchestrated by osteogenesis of osteoblasts and osteoclastogenesis of osteoclasts, maintains the homeostasis of osteal development and metabolism under physiological conditions. Bone morphogenetic protein receptor type 1A, also known as activin receptor-like kinase 3 (ALK3), which exists on cytomembrane, is one of the key receptors of BMP factors, and is an important "gateway" that regulates the entrance of BMP signaling into cells in order to perform biological functions. The roles of BMP signaling in bone remodeling have been extensively studied. Many new discoveries have been reported in recent years through research based on transgenic mice models and focused on ALK3 as targets, shedding new light on the regulations of bone remodeling, cartilage and joint development, and the occurrence and treatment of bone-related diseases. Established understanding has been expanded, but new challenges on existing clinical application of BMPs also appeared. Hence, we reviewed recent studies on ALK3's involvement in bone formation and bone resorption, analyzed its mechanism of action in bone regulation, summarized the roles of ALK3 in the development of cartilage and temporomandibular joint, and reported the latest progress in treatment in preclinical studies, intending to provide references for subsequent studies and clinical applications in the future.

Lipid-Based Nano-Sized Cargos as a Promising Strategy in Bone Complications: A Review.

Bone metastasis has been considered the fatal phase of cancers, which remains incurable and to be a challenge due to the non-availability of the ideal treatment strategy. Unlike bone cancer, bone metastasis involves the spreading of the tumor cells to the bones from different origins. Bone metastasis generally originates from breast and prostate cancers. The possibility of bone metastasis is highly attributable to its physiological milieu susceptible to tumor growth. The treatment of bone-related diseases has multiple complications, including bone breakage, reduced quality of life, spinal cord or nerve compression, and pain. However, anticancer active agents have failed to maintain desired therapeutic concentrations at the target site; hence, uptake of the drug takes place at a non-target site responsible for the toxicity at the cellular level. Interestingly, lipid-based drug delivery systems have become the center of interest for researchers, thanks to their biocompatible and bio-mimetic nature. These systems possess a great potential to improve precise bone targeting without affecting healthy tissues. The lipid nano-sized systems are not only limited to delivering active agents but also genes/peptide sequences/siRNA, bisphosphonates, etc. Additionally, lipid coating of inorganic nanomaterials such as calcium phosphate is an effective approach against uncontrollable rapid precipitation resulting in reduced colloidal stability and dispersity. This review summarizes the numerous aspects, including development, design, possible applications, challenges, and future perspective of lipid nano-transporters, namely liposomes, exosomes, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and lipid nanoparticulate gels to treat bone metastasis and induce bone regeneration. Additionally, the economic suitability of these systems has been discussed and different alternatives have been discussed. All in all, through this review we will try to understand how far nanomedicine is from clinical and industrial applications in bone metastasis.

Recent Advances in Osteoclast Biological Behavior.

With the progress of the aging population, bone-related diseases such as osteoporosis and osteoarthritis have become urgent problems. Recent studies have demonstrated the importance of osteoclasts in bone homeostasis, implying these will be an important mediator in the treatment of bone-related diseases. Up to now, several reviews have been performed on part of osteoclast biological behaviors such as differentiation, function, or apoptosis. However, few reviews have shown the complete osteoclast biology and research advances in recent years. Therefore, in this review, we focus on the origin, differentiation, apoptosis, behavior changes and coupling signals with osteoblasts, providing a simple but comprehensive overview of osteoclasts for subsequent studies.

Macrophage-Osteoclast Associations: Origin, Polarization, and Subgroups.

Cellular associations in the bone microenvironment are involved in modulating the balance between bone remodeling and resorption, which is necessary for maintaining a normal bone morphology. Macrophages and osteoclasts are both vital components of the bone marrow. Macrophages can interact with osteoclasts and regulate bone metabolism by secreting a variety of cytokines, which make a significant contribution to the associations. Although, recent studies have fully explored either macrophages or osteoclasts, indicating the significance of these two types of cells. However, it is of high importance to report the latest discoveries on the relationships between these two myeloid-derived cells in the field of osteoimmunology. Therefore, this paper reviews this topic from three novel aspects of the origin, polarization, and subgroups based on the previous work, to provide a reference for future research and treatment of bone-related diseases.

Safety of Denosumab Versus Zoledronic Acid in Patients with Bone-related Diseases A Systematic Review and Meta-analysis

IntroductionBoth Dmab and ZA have been widely used in the prevention and treatment of bone-related diseases, while which drug is an optimal treatment in terms of safety and efficacy remains controversial.Material and methodsPubMed, Embase, Web of Science, the Cochrane Central Library, and ClinicalTrials.gov were systematically searched up to 1st January 2021, and were evaluated by Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Randomized controlled trials comparing Dmab versus ZA in patients with bone-related diseases were included.ResultsA total of 13 studies involving 21042 participants were included. The incidence of total adverse events was significantly lower in patients receiving Dmab treatment than in those undergoing ZA treatment(OR= 0.84, 95% CI = 0.75–0.94, P = 0.003). 9 trials comparing Dmab with ZA further showed that Dmab was significantly better than ZA in controlling serious adverse events (OR = 0.91, 95% CI = 0.85–0.99, P = 0.02). Compared to ZA, Dmab was correlated with a lower incidence of skeletal-related events (OR = 0.77, 95% CI = 0.70–0.85, P = 0.00001). However, no significant difference was found in the rate of infection events between Dmab and ZA (OR = 1.06, 95% CI = 0.93–1.20, P =0.39).ConclusionsThis study demonstrated superiority of Dmab over ZA in treating bone-related diseases in terms of safety and efficacy.

Insight into the roles of melatonin in bone tissue and bone‑related diseases (Review).

Bone-related diseases comprise a large group of common diseases, including fractures, osteoporosis and osteoarthritis (OA), which affect a large number of individuals, particularly the elderly. The progressive destruction and loss of alveolar bone caused by periodontitis is a specific type of bone loss, which has a high incidence and markedly reduces the quality of life of patients. With the existing methods of prevention and treatment, the incidence and mortality of bone-related diseases are still gradually increasing, creating a significant financial burden to societies worldwide. To prevent the occurrence of bone-related diseases, delay their progression or reverse the injuries they cause, new alternative or complementary treatments need to be developed. Melatonin exerts numerous physiological effects, including inducing anti-inflammatory and antioxidative functions, resetting circadian rhythms and promoting wound healing and tissue regeneration. Melatonin also participates in the health management of bone and cartilage. In the present review, the potential roles of melatonin in the pathogenesis and progression of bone injury, osteoporosis, OA and periodontitis are summarized. Furthermore, the high efficiency and diversity of the physiological regulatory effects of melatonin are highlighted and the potential benefits of the use of melatonin for the clinical prevention and treatment of bone-related diseases are discussed.

Induction of osteogenesis in bone tumour cells by purine-conjugated zinc-hydroxyapatite

This study aimed to improve the biocompatibility and osteogenic property of hydroxyapatite (HAP). So HAP nanoparticles were doped with zinc (Zn), and their surface was modified with a purine nucleotide, guanosine 5′-triphosphate (GTP). GTP-loaded nanoparticles (GTP@ZnHAP) were characterised by field emission scanning electron microscopy, Fourier transform infrared, thermogravimetric analysis, zeta potential and ultraviolet–visible spectroscopy. Biological experiments revealed that GTP@ZnHAP nanoparticles were internalised by the cells, inhibiting tumour cell (osteoblast-like cells, Saos-2) expansion with an efficiency more than that observed for ZnHAP nanoparticles and GTP alone. Furthermore, Saos-2 cells were committed to differentiate into the normal osteoblast cells under the influence of GTP@ZnHAP nanoparticles demonstrated by the quantitative assessment of bone-related protein expression (Runx2 and osteocalcin) and cell morphological changes. Moreover, high-performance liquid chromatography analyses disclosed a significant enhancement of intracellular GTP content in GTP@ZnHAP-treated cells, proposing perturbation of intracellular nucleotide equilibrium during the process of osteogenesis induced by GTP@ZnHAP nanoparticles. Overall, GTP@ZnHAP exhibits a better synergistic effect on the modulation of cell growth and induction of osteogenic differentiation in osteosarcoma cells than ZnHAP nanoparticles and GTP alone do. Therefore, GTP@ZnHAP may be regarded as a promising biomaterial for the treatment of bone-related diseases.

Therapeutic and Mechanistic Approaches of Tridax Procumbens Flavonoids for the Treatment of Osteoporosis.

Homeostasis of bone is closely regulated by the balanced activities between the bone resorbing activity of osteoclast cells and bone-forming ability of osteoblast cells. Multinucleated osteoclasts degrade bone matrix and involve in the dynamic bone remodelling in coordination with osteoblasts. Disruption of this regulatory balance between these cells or any imbalance in bone remodelling caused by a higher rate of resorption over construction of bone results in a decrease of bone matrix including bone mineral density (BMD). These osteoclast-dominant effects result in a higher risk of bone crack and joint demolition in several bone-related diseases, including osteoporosis and rheumatoid arthritis (RA). Tridax procumbens is a very interesting perennial plant and its secondary metabolites called here T. procumbens flavonoids (TPFs) are well-known phytochemical agents owing to various therapeutic practices such as anti-inflammatory, anti-anaemic and anti-diabetic actions. This review designed to focus the systematic convention concerning the medicinal property and mechanism of actions of TPFs for the management of bone-related diseases. Based on the current literature, the review offers evidence-based information of TPFs for basic researchers and clinicians for the prevention and treatment of bone related diseases, including osteoporosis. It also emphasizes the medical significance for more research to comprehend the cellular signalling pathways of TPFs for the regulation of bone remodelling and discusses the possible promising ethnobotanical resource that can convey the preclinical and clinical clues to develop the next generation therapeutic agents for the treatment of bonerelated disorders.

Matrix Metalloproteinase Inspired Therapeutic Strategies for Bone Diseases.

Matrix Metalloproteinases (MMPs), as a family of zinc-containing enzymes, show the function of decomposing Extracellular Matrix (ECM) and participate in the physiological processes of cell migration, growth, inflammation, and metabolism. Clinical and experimental studies have indicated that MMPs play an essential role in tissue injury and repair as well as tumor diagnosis, metastasis, and prognosis. An increasing number of researchers have paid attention to their functions and mechanisms in bone health and diseases. The present review focuses on MMPs-inspired therapeutic strategies for the treatment of bone-related diseases. We introduce the role of MMPs in bone diseases, highlight the MMPs-inspired therapeutic options, and posit MMPs as a trigger for smart cell/drug delivery.

Long non-coding RNA H19 promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells by regulating microRNA-140-5p/SATB2 axis

The osteogenic differentiation of mesenchymal stem cells (MSCs) has potential clinical values in the treatment of bone-related diseases. Long non-coding RNA H19 and microRNA-140-5p (miR-140-5p) have attracted much attention of researchers by virtue of their biological importance in cell differentiation and bone formation. Moreover, bioinformatics analyses suggest that miR-140-5p have the potential to bind with H19 and SATB homeobox 2 (SATB2). In this study, we further explored whether H19 could regulate osteogenic differentiation of human bone marrow-derived MSCs (BM-MSCs) by miR-140-5p/SATB2 axis. RT-qPCR assay was conducted to examine the expression of H19, miR-140-5p and SATB2. The osteogenic differentiation capacity of BM-MSCs was assessed through alkaline phosphatase (ALP) activity and osteogenic marker expression. The relationships among H19, miR-140-5p and SATB2 were examined through bioinformatics analyses, luciferase reporter assay, RIP assay and RNA pull-down assay. H19 expression was remarkably increased and miR-140-5p expression was dramatically reduced during osteogenic differentiation of BMMSCs. Functional analyses revealed that H19 overexpression or miR-140-5p depletion accelerated osteogenic differentiation of BM-MSCs. Conversely, H19 loss or miR-140-5p increase suppressed osteogenic differentiation of BM-MSCs. MiR-140-5p was confirmed as a target of H19, and miR-140-5p could bind to SATB2 as well. Moreover, H19 knockdown reduced SATB2 expression by upregulating miR-140-5p. Additionally, miR140-5p depletion antagonized the inhibitory effect of H19 knockdown on osteogenic differentiation of BMMSCs. And, miR-140-5p inhibited osteogenic differentiation of BM-MSCs by targeting SATB2. In conclusion, H19 promoted osteogenic differentiation of BM-MSCs through regulating miR-140-5p/SATB2 axis, deepening our understanding on the molecular mechanisms of H19 in coordinating osteogenesis.

NMR for screening and a biochemical assay: Identification of new FPPS inhibitors exerting anticancer activity.

Farnesyl pyrophosphate synthase (FPPS) is a crucial enzyme for the synthesis of isoprenoids and the key target of nitrogen-containing bisphosphonates (N-BPs). N-BPs are potent and selective FPPS inhibitors that are used in the treatment of bone-related diseases, but have poor pharmacokinetic properties. Given the key role played by FPPS in many cancer-related pathways and the pharmacokinetic limits of N-BPs, hundreds of molecules have been screened to identify new FPPS inhibitors characterized by improved drug-like properties that are useful for broader therapeutic applications in solid, non-skeletal tumours. We have previously shown that N6-isopentenyladenosine (i6A) and its related compound N6-benzyladenosine (2) exert anti-glioma activity by interfering with the mevalonate pathway and inhibiting FPPS. Here, we report the design and synthesis of a panel of N6-benzyladenosine derivatives (compounds 2a-m) incorporating different chemical moieties on the benzyl ring. Compounds 2a-m show in vitro antiproliferative activity in U87MG glioma cells and, analogous to the bisphosphonate FPPS inhibitors, exhibit immunogenic properties in ex vivo γδ T cells from stimulated peripheral blood mononuclear cells (PBMCs). Using saturation transfer difference (STD) and quantitative 1H nuclear magnetic resonance (NMR) experiments, we found that 2f, the N6-benzyladenosine analogue that includes a tertbutyl moiety in the para position of the benzyl ring, is endowed with increased FPPS binding and inhibition compared to the parent compounds i6A and 2. N6-benzyladenosine derivatives, characterized by structural features that are significantly different from those of N-BPs, have been confirmed to be promising chemical scaffolds for the development of non N-BP FPPS inhibitors, exerting combined cytotoxic and immunostimulatory activities.

Hexane Fraction of Turbo brunneus Inhibits Intermediates of RANK-RANKL Signaling Pathway and Prevent Ovariectomy Induced Bone Loss.

Osteoporosis is a “silent disease” characterized by fragile and impaired bone quality. Bone fracture results in increased mortality and poor quality of life in aged people particularly in postmenopausal women. Bone is maintained through the delicate balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. The imbalance is caused most often by overly active osteoclasts due to estrogen deficiency. Natural products have long been used to prevent and treat osteoporosis since they have fewer side effects. The marine environment is a potential source of biologically and structurally novel biomolecules with promising biological activities but is less explored for the treatment of bone-related diseases. The present study aims to evaluate the antiosteoporotic effect of Hexane fraction of Turbo brunneus methanolic extract (HxTME) and to investigate its role in RANK-RANKL signaling pathway using in vitro osteoclasts cultures and in vivo ovariectomized (OVX) Swiss mice model. The present study demonstrated that the HxTME significantly inhibited RANKL induced osteoclast differentiation and maturation in vitro. HxTME completely downregulated the mRNA expression of key transcription factors such as NFATc1, c-FOS, and osteoclasts related genes involved in osteoclastogenesis. In vivo studies also depicted the effectiveness of HxTME in ovariectomized mice by preserving bone microarchitecture, mineral content, and inhibiting bone loss in treated mice as analyzed by Histomorphometry, MicroCT, and Raman spectroscopy. Oral administration of HxTME fraction resulted in the decreased percentage of F4/80+, CD11b+, and CD4+ RANKL+ T cells in OVX mice whereas pro-osteoclastic cytokine, IL6 was markedly reduced upon treatment with HxTME. On stimulation with PMA/Io and PHA, a significant decrease in proliferative response in the splenocytes of HxTME treated OVX mice was observed. Fatty acid profiling revealed that HxTME is rich in ω3 and ω6 polyunsaturated fatty acids (PUFAs), which have high nutraceutical properties and are known to play important role in growth, development and maintenance of health. Therefore, HxTME may be a good source of nutraceutical in the treatment of bone-related diseases particularly in postmenopausal osteoporosis and may be pursued as a potential candidate for treatment and management of osteoporosis.

Progress of research on the relationship between calcitonin gene-related peptide and RANK/RANKL/OPG system in the bone reconstruction

To summarize the research progress on the calcitonin gene-related peptide (CGRP) and receptor activator of nuclear factor κB (RANK)/receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) system during bone reconstruction to provide theoretical basis for further research on the prevention and treatment of bone-related diseases. The relevant research results at home and abroad in recent years were analyzed and summarized. CGRP and RANK/RANKL/OPG system play important regulatory roles in the bone reconstruction. At present, the research on the mechanism of CGRP and RANK/RANKL/OPG system in bone reconstruction is insufficient. Therefore, it is necessary to study further on the process and interrelation of CGRP and RANK/RANKL/OPG system in bone reconstruction to confirm their mechanism, which will bring new ideas and methods for the treatment of bone related diseases in clinic.

Micrornas at the Interface between Osteogenesis and Angiogenesis as Targets for Bone Regeneration.

Bone formation and regeneration is a multistep complex process crucially determined by the formation of blood vessels in the growth plate region. This is preceded by the expression of growth factors, notably the vascular endothelial growth factor (VEGF), secreted by osteogenic cells, as well as the corresponding response of endothelial cells, although the exact mechanisms remain to be clarified. Thereby, coordinated coupling between osteogenesis and angiogenesis is initiated and sustained. The precise interplay of these two fundamental processes is crucial during times of rapid bone growth or fracture repair in adults. Deviations in this balance might lead to pathologic conditions such as osteoarthritis and ectopic bone formation. Besides VEGF, the recently discovered important regulatory and modifying functions of microRNAs also support this key mechanism. These comprise two principal categories of microRNAs that were identified with specific functions in bone formation (osteomiRs) and/or angiogenesis (angiomiRs). However, as hypoxia is a major driving force behind bone angiogenesis, a third group involved in this process is represented by hypoxia-inducible microRNAs (hypoxamiRs). This review was focused on the identification of microRNAs that were found to have an active role in osteogenesis as well as angiogenesis to date that were termed “CouplingmiRs (CPLGmiRs)”. Outlined representatives therefore represent microRNAs that already have been associated with an active role in osteogenic-angiogenic coupling or are presumed to have its potential. Elucidation of the molecular mechanisms governing bone angiogenesis are of great relevance for improving therapeutic options in bone regeneration, tissue-engineering, and the treatment of bone-related diseases.

Bisphosphonate inhibits the expression of cyclinA2 at the transcriptional level in normal human oral keratinocytes.

Nitrogen-containing bisphosphonates (N-BPs) are the most widely used anti-resorptive agents in the treatment of bone-related diseases. N-BPs inhibit bone resorption by specifically targeting osteoclasts, bone-resorbing cells. However, soft tissue toxicity, such as oral or gastrointestinal (GI) ulcerations has frequently been reported in N-BP users, suggesting that N-BPs may also directly target cells other than osteoclasts. Previously, we reported that BPs inhibit proliferation without inducing the apoptosis of normal human oral keratinocytes (NHOKs). However, the molecular mechanisms through which N-BPs inhibit the proliferation of NHOKs are not yet fully understood. In this study, we performed gene expression profiling in N-BP-treated NHOKs and identified cyclin A2 as one of the most commonly downregulated genes. When the NHOKs were treated with N-BPs, we found that the level of cyclin A2 was suppressed in a dose- and time-dependent manner. In addition, the protein level of cyclin A2 was also significantly lower in oral epithelial cells in N-BP-treated oral mucosal tissue constructs. Cyclin A2 promoter reporter assay revealed that N-BPs inhibited the luciferase activity, indicating that the inhibition of cyclin A2 expression occurs at the transcriptional level. Furthermore, N-BPs did not alter the expression of cyclin A2 in normal human oral fibroblasts (NHOFs), suggesting that the effect of N-BPs on cyclin A2 expression may be cell-type specific. Thus, the findings of our study demonstrate that the inhibition of NHOK proliferation by N-BPs is mediated, at least in part, by the suppression of cyclin A2 expression at the transcriptional level, which may explain the underlying mechanisms of soft tissue toxicity by N-BPs.

Role of apoptosis in pathogenesis and treatment of bone-related diseases.

In this article, bone cells and their intercellular communications have been reviewed. Gap junctions and hemichannels are the main routes of interactions in bone tissue. They play a substantial role in survival and cell death, since pro-apoptotic signals can propagate through them. Different adhesion molecules are required for apoptosis, particularly caspase family as well as noncaspase proteases. The disruption outcome of apoptosis could result in bone-related diseases such as osteonecrosis. Anti-apoptotic strategies include inhibition of caspase, poly [ADP-ribose] polymerase (PARP), and Bcl-2 proteins as well as induction of the PKB/Akt pathway and inhibitors of apoptosis (IAP) family of proteins. Thus, understanding the mechanism of apoptosis gives detailed insights of anti-apoptotic molecular targets. Based on these targets, different treatments were designed and produced such as estrogen replacement therapy, administration of different bisphosphonates, raloxifene, calcitonin, sodium fluoride, calcium, and vitamin D. As a result, new applicable drugs for treatment of related bone problems can be proposed for clinical approach especially in the early stage of diseases.

Current View on Osteogenic Differentiation Potential of Mesenchymal Stromal Cells Derived from Placental Tissues.

Mesenchymal stromal cells (MSC) isolated from human term placental tissues possess unique characteristics, including their peculiar immunomodulatory properties and their multilineage differentiation potential. The osteogenic differentiation capacity of placental MSC has been widely disputed, and continues to be an issue of debate. This review will briefly discuss the different MSC populations which can be obtained from different regions of human term placenta, along with their unique properties, focusing specifically on their osteogenic differentiation potential. We will present the strategies used to enhance osteogenic differentiation potential in vitro, such as through the selection of subpopulations more prone to differentiate, the modification of the components of osteo-inductive medium, and even mechanical stimulation. Accordingly, the applications of three-dimensional environments in vitro and in vivo, such as non-synthetic, polymer-based, and ceramic scaffolds, will also be discussed, along with results obtained from pre-clinical studies of placental MSC for the regeneration of bone defects and treatment of bone-related diseases.