To defense harmful stimuli or maintain the immune homeostasis, the body produces and recruits a superfamily of cytokines such as interleukins, interferons, chemokines etc. Among them, chemokines act as crucial regulators in defense systems. CCL5/CCR5 combination is known for facilitating inflammatory responses, as well as inducing the adhesion and migration of different T cell subsets in immune responses. In addition, recent studies have shown that the interaction between CCL5 and CCR5 is involved in various pathological processes including inflammation, chronic diseases, cancers as well as the infection of COVID-19. This review focuses on how CCL5/CCR5 axis participates in the pathological processes of different diseases and their relevant signaling pathways for the regulation of the axis. Moreover, we highlighted the gene therapy and chemotherapy studies for treating CCR5-related diseases, including the ongoing clinical trials. The barriers and perspectives for future application and translational research were also summarized.

CCL5/CCR5 axis in human diseases and related treatments.

Mesenchymal stem cells (MSCs) have been identified in many adult tissues. MSCs can regenerate through cell division or differentiate into adipocytes, osteoblasts and chondrocytes. As a result, MSCs have become an important source of cells in tissue engineering and regenerative medicine for bone tissue and cartilage. Several epigenetic factors are believed to play a role in MSCs differentiation. Among these, microRNA (miRNA) regulation is involved in the fine modulation of gene expression during osteogenic/chondrogenic differentiation. It has been reported that miRNAs are involved in bone homeostasis by modulating osteoblast gene expression. In addition, countless evidence has demonstrated that miRNAs dysregulation is involved in the development of osteoporosis and bone fractures. The deregulation of miRNAs expression has also been associated with several malignancies including bone cancer. In this context, bone-associated circulating miRNAs may be useful biomarkers for determining the predisposition, onset and development of osteoporosis, as well as in clinical applications to improve the diagnosis, follow-up and treatment of cancer and metastases. Overall, this review will provide an overview of how miRNAs activities participate in osteogenic/chondrogenic differentiation, while addressing the role of miRNA regulatory effects on target genes. Finally, the role of miRNAs in pathologies and therapies will be presented.

The role of microRNAs in the osteogenic and chondrogenic differentiation of mesenchymal stem cells and bone pathologies.

Bone marrow mesenchymal stem cells (BMSCs) exhibit the capacity to self-renew and differentiate into multi-lineage cell types, including osteoblasts, which are crucial regulators of fracture healing. Thus, this study aims to investigate the effect of microRNA (miR)-22-3p from BMSC-derived EVs on osteogenic differentiation and its underlying mechanism. Extracellular vesicles (EVs) were isolated from BMSCs and taken up with BMSCs. Dual-luciferase reporter gene assay was used to verify the binding relationship between miR-22-3p and FTO. Loss- and gain-of-function experiments were performed to determine the roles of EV-delivered miR-22-3p and FTO in osteogenic differentiation as well as their regulatory role in the MYC/PI3K/AKT axis. To determine the osteogenic differentiation, ALP and ARS stainings were conducted, and the levels of RUNX2, OCN, and OPN level were determined. In vivo experiment was conducted to determine the function of EV-delivered miR-22-3p and FTO in osteogenic differentiation, followed by ALP and ARS staining. miR-22-3p expression was repressed, while FTO expression was elevated in the ovariectomized mouse model. Overexpression of miR-22-3p, EV-delivered miR-22-3p, increased ALP activity and matrix mineralization of BMSCs and promoted RUNX2, OCN, and OPN expressions in BMSCs. miR-22-3p negatively targeted FTO expression. FTO silencing rescued the suppressed osteogenic differentiation by EV-delivered miR-22-3p inhibitor. FTO repression inactivated the MYC/PI3K/AKT pathway, thereby enhancing osteogenic differentiation both in vivo and in vitro. In summary, miR-22-3p delivered by BMSC-derived EVs could result in the inhibition of the MYC/PI3K/AKT pathway, thereby promoting osteogenic differentiation via FTO repression.

/pdf/extracellular-vesicle-encapsulated-mir-22-3p-from-bone-19atmgkb8d.pdf

Extracellular vesicle-encapsulated miR-22-3p from bone marrow mesenchymal stem cell promotes osteogenic differentiation via FTO inhibition.

Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age-matched persons without diabetes, attributed to disease-specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin-based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall-related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo-anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium-dependent glucose co-transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes-related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

Diabetes pharmacotherapy and effects on the musculoskeletal system

To defense harmful stimuli or maintain the immune homeostasis, the body produces and recruits a superfamily of cytokines such as interleukins, interferons, chemokines etc. Among them, chemokines act as crucial regulators in defense systems. CCL5/CCR5 combination is known for facilitating inflammatory responses, as well as inducing the adhesion and migration of different T cell subsets in immune responses. In addition, recent studies have shown that the interaction between CCL5 and CCR5 is involved in various pathological processes including inflammation, chronic diseases, cancers as well as the infection of COVID-19. This review focuses on how CCL5/CCR5 axis participates in the pathological processes of different diseases and their relevant signaling pathways for the regulation of the axis. Moreover, we highlighted the gene therapy and chemotherapy studies for treating CCR5-related diseases, including the ongoing clinical trials. The barriers and perspectives for future application and translational research were also summarized. 

CCL5/CCR5 axis in human diseases and related treatments

Certain microRNAs (miRs) have important roles in the maintenance of bone development and metabolism, and a variety of miRs are known to be deregulated in diabetes. The present study investigated the role of miR‑203‑3p in the regulation of bone loss by assessing jaw bones of a rat model of type 2 diabetes. The results indicated that miR‑203‑3p inhibited osteogenesis in the jaws of diabetic rats and in rat bone marrow mesenchymal stem cells cultured in high‑glucose medium. A luciferase re-porter assay was used to verify the bioinformatics prediction that miR‑203‑3p targets the 3'‑untranslated region of Smad1, which is an important mediator of the bone morphogenetic protein (BMP)/Smad pathway. Overexpression of Smad1 attenuated the miR‑203‑3p‑mediated suppres-sion of osteogenic differentiation. It was therefore indicated that the BMP/Smad pathway is attenuated and the transforming growth factor‑β/activin pathway is promoted by Smad1 reduction. Taken together, it was indicated that miR‑203‑3p inhibits osteogenesis in jaw bones of diabetic rats by targeting Smad1 to inhibit the BMP/Smad pathway.

/pdf/mir-203-3p-participates-in-the-suppression-of-diabetes-59292x1urh.pdf

miR‑203‑3p participates in the suppression of diabetes‑associated osteogenesis in the jaw bone through targeting Smad1.

Osteogenesis is mediated by sophisticated interactions of various molecular functions and biological processes, including post-transcriptional regulation. A range of miRNAs have been reported to regulate bone homeostasis and osteoblasts differentiation either positively or negatively through multiple signaling pathways. RNase III endonuclease Dicer is the key enzyme required for the biogenesis of miRNAs and small interfering RNAs. To determine the global influence of miRNAs on regulation of osteogenesis of pre-osteoblast cells, the transcriptional regulation of Dicer and the function of Dicer during osteoblast differentiation and mineralization were investigated. Runx2 binding directly to the Dicer promoter region was characterized in MC3T3-E1 cells by chromatin immunoprecipitation (ChIP) and luciferase promoter reporter assays. Overexpression or knockdown of Runx2 resulted in increase or decrease of Dicer expression, respectively. Furthermore, abatement of Dicer in MC3T3-E1 cells down-regulated the expression of osteogenic marker genes and mineralization ability, at least partly involving Dicer-dependent processing of the miR-21a-5p targeting PTEN via pAKT/pGSK3β/β-catenin signaling pathways. Taken together, the study demonstrates the role of Dicer in osteogenesis and suggests that Dicer is required, in part, for Runx2 regulation of osteoblast differentiation.

Dicer-dependent pathway contribute to the osteogenesis mediated by regulation of Runx2.

Background Mesenchymal stem cells (MSCs) differentiate into osteocytes, adipocytes, and chondrocytes. Resveratrol and bone morphogenetic protein 9 (BMP9) are known osteogenic induction factors of MSCs, but the effect of both resveratrol and BMP9 on osteogenesis is unknown. Herein, we explored whether resveratrol cooperates with BMP9 to improve osteogenic induction. Methods The osteogenic induction of resveratrol and BMP9 on C3H10T1/2 cells was evaluated by detecting the staining and activity of the early osteogenic marker alkaline phosphatase (ALP). In addition, the late osteogenic effect was measured by the mRNA and protein levels of osteogenic markers, such as osteopontin (OPN) and osteocalcin (OCN). To assess the bone formation function of resveratrol plus BMP9 in vivo, we transplanted BMP9-infected C3H10T1/2 cells into nude mice followed by intragastric injection of resveratrol. Western blot (WB) analysis was utilized to elucidate the mechanism of resveratrol plus BMP9. Results Resveratrol not only enhanced osteogenic induction alone but also improved BMP9-induced ALP at 3, 5, and 7 d postinduction. Both the early osteogenic markers (ALP, Runx2, and SP7) and the late osteogenic markers (OPN and OCN) were significantly increased when resveratrol was combined with BMP9. The fetal limb explant culture further verified these results. The in vivo bone formation experiment, which involved transplanting BMP9-overexpressing C3H10T1/2 cells into nude mice, also confirmed that resveratrol synergistically enhanced the BMP9-induced bone formation function. Resveratrol phosphorylated adenosine monophosphate- (AMP-) activated protein kinase (AMPK) and stimulated autophagy, but these effects were abolished by inhibiting AMPK and Beclin1 using an inhibitor or siRNA. Conclusions Resveratrol combined with BMP9 significantly improves the osteogenic induction of C3H10T1/2 cells by activating AMPK and autophagy.

/pdf/resveratrol-synergistically-promotes-bmp9-induced-osteogenic-gofxpyr0.pdf

Resveratrol Synergistically Promotes BMP9-Induced Osteogenic Differentiation of Mesenchymal Stem Cells

In order to estimate the adaptability of Agricultural Production Systems Simulator (APSIM)-Maize model under the special climate environment in tropic, 10 field experiments were conducted at different seasons in three sites (Longchuan, Mangshi and Ruili) of tropic in Yunnan Province, China. The parameters of APSIM model were calibrated and its adaptability was validated. The results showed that the days from sowing to flowering and sowing to maturity were predicted accurately for all sites with mean errors of 2.0 Â± 0.4, and 3.2 Â± 0.7 d respectively. The normalized root mean square errors (NRMSE) of the model for yield prediction were 2%, 3% and 5% for each of three sites, respectively, which indicated that the APSIM model had good accuracy and sensitivity in predicting phenological phases and yield of maize (Zea mays L.) grown in different seasons, and the model had good adaptability in the tropic of Southwest China. This study provided the basis and technical support for evaluating maize production potential based on the model. 

Calibration and validation of APSIM for maize grown in different seasons in Southwest tropic of China

OBJECTIVES To study the characteristics of bone in type 2 diabetic rats using micro-CT. METHODS Sixteen male Sprague Dawley(SD) rats, aged 8 week-old, were randomly divided into normal group and experimental group (n =10). Afer being fed with high-fat chow, the rats in experimental group were given low-dose streptozotocin (STZ,30 mg/kg) to induce type 2 diabetic disease. Serum glucose, insulin and tissue sections of pancreas is used to evaluate the effect of type 2 diabetic rat model. The characteristics of bone in the two groups were measured and compared by micro-CT. RESULTS Compared with normal group (n =10), the experimental group (n =9) had the body mass and serum glucose increased significantly (P 0.05). Pancreatic tissue section staining showed in experimental group islet morphology was irregular, edge boundary was blur and islet cells were saperated with increasing fiber tissue. The bone volume of normal and experimental groups were (0.194 2±2.332)%, and (0.080 7±1.952)%, respectively. Trabecular thickness (unit:mm) were 0.052 9±0.004 5 and 0.043 6±0.002 4, respectively. Trabecular number (unit:mm⁻¹) were 3.668 8±0.134 5, and 1.851 7±0.288 8, respectively ( P<0.05), while trabecular space (unit:mm) were 0.219 6±0.072 1 and 0.496 5±0.076 4, respectively( P<0.05). Bone tissue morphology metrology test results was consistent with the results of micro-CT. CONCLUSIONS The diabetic rat model showed declined bone volume and trabecular density, trabecular number. Micro-CT may be more intuitive in bone quality inspection to reflect the characteristics of bone microstructure morphology.

[Study on the Characteristics of Bone in Type-2 Diabetic Rats by Micro-CT].

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