Canonical Wnt signaling regulates soft palate development by mediating ciliary homeostasis.

Craniofacial morphogenesis requires complex interactions involving different tissues, signaling pathways, secreted factors and organelles. The details of these interactions remain elusive. In this study, we have analyzed the molecular mechanisms and homeostatic cellular activities governing soft palate development to improve regenerative strategies for individuals with cleft palate. We have identified canonical Wnt signaling as a key signaling pathway primarily active in cranial neural crest (CNC)-derived mesenchymal cells surrounding soft palatal myogenic cells. Using Osr2-Cre;ß-cateninfl/fl mice, we show that Wnt signaling is indispensable for mesenchymal cell proliferation and subsequently for myogenesis through mediating ciliogenesis. Specifically, we have identified that Wnt signaling directly regulates expression of the ciliary gene Ttll3. Impaired ciliary disassembly leads to differentiation defects in mesenchymal cells and indirectly disrupts myogenesis through decreased expression of Dlk1, a mesenchymal cell-derived pro-myogenesis factor. Moreover, we show that siRNA-mediated reduction of Ttll3 expression partly rescues mesenchymal cell proliferation and myogenesis in the palatal explant cultures from Osr2-Cre;ß-cateninfl/fl embryos. This study highlights the role of Wnt signaling in palatogenesis through the control of ciliary homeostasis, which establishes a new mechanism for Wnt-regulated craniofacial morphogenesis.

TGF-ß signaling and Creb5 cooperatively regulate Fgf18 to control pharyngeal muscle development.

The communication between myogenic cells and their surrounding connective tissues is indispensable for muscle morphogenesis. During late embryonic development in mice, myogenic progenitors migrate to discrete sites to form individual muscles. The detailed mechanism of this process remains unclear. Using mouse levator veli palatini (LVP) development as a model, we systematically investigated how a distinct connective tissue subpopulation, perimysial fibroblasts, communicates with myogenic cells to regulate mouse pharyngeal myogenesis. Using single-cell RNAseq data analysis, we identified that TGF-ß signaling is a key regulator for the perimysial fibroblasts. Loss of TGF-ß signaling in the neural crest-derived palatal mesenchyme leads to defects in perimysial fibroblasts and muscle malformation in the soft palate in Osr2Cre;Tgfbr1fl/fl mice. In particular, Creb5, a transcription factor expressed in the perimysial fibroblasts, cooperates with TGF-ß signaling to activate expression of Fgf18. Moreover, Fgf18 supports pharyngeal muscle development in vivo and exogenous Fgf18 can partially rescue myogenic cell numbers in Osr2Cre;Tgfbr1fl/fl samples, illustrating that TGF-ß-regulated Fgf18 signaling is required for LVP development. Collectively, our findings reveal the mechanism by which TGF-ß signaling achieves its functional specificity in defining the perimysial-to-myogenic signals for pharyngeal myogenesis.

Activation of the Renin-Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes.

High blood pressure is one of the major public health problems that causes severe disorders in several tissues including the human kidney. One of the most important signaling pathways associated with the regulation of blood pressure is the renin-angiotensin system (RAS), with its main mediator angiotensin II (ANGII). Elevated levels of circulating and intracellular ANGII and aldosterone lead to pro-fibrotic, -inflammatory, and -hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Furthermore, ANGII has been recognized as a major risk factor for the induction of apoptosis in podocytes, ultimately leading to chronic kidney disease (CKD). In the past, disease modeling of kidney-associated diseases was extremely difficult, as the derivation of kidney originated cells is very challenging. Here we describe a differentiation protocol for reproducible differentiation of sine oculis homeobox homolog 2 (SIX2)-positive urine-derived renal progenitor cells (UdRPCs) into podocytes bearing typical cellular processes. The UdRPCs-derived podocytes show the activation of the renin-angiotensin system by being responsive to ANGII stimulation. Our data reveal the ANGII-dependent downregulation of nephrin (NPHS1) and synaptopodin (SYNPO), resulting in the disruption of the podocyte cytoskeletal architecture, as shown by immunofluorescence-based detection of α-Actinin. Furthermore, we show that the cytoskeletal disruption is mainly mediated through angiotensin II receptor type 1 (AGTR1) signaling and can be rescued by AGTR1 inhibition with the selective, competitive angiotensin II receptor type 1 antagonist, losartan. In the present manuscript we confirm and propose UdRPCs differentiated to podocytes as a unique cell type useful for studying nephrogenesis and associated diseases. Furthermore, the responsiveness of UdRPCs-derived podocytes to ANGII implies potential applications in nephrotoxicity studies and drug screening.

Human bone and amniotic membrane banking in Bangladesh for grafting: the impact of the international atomic energy agency (IAEA) programme.

The idea of establishing a human tissue bank in Bangladesh was started in 1985. However, in 2003, with the active cooperation of international atomic energy agency (IAEA) and Bangladesh Atomic Energy Commission, a tissue bank laboratory was upgraded as a unit for tissue banking and research. Due to increasing demand of allograft, this unit was transformed as an independent institute "Institute of Tissue Banking and Biomaterial Research (ITBBR)" in 2016. This is the only human tissue bank in Bangladesh, which processes human bone and amniotic membrane to provide safe and cost-effective allografts for transplantation. Importantly, banking of human cranial bone as autograft has also started at ITBBR. These processed grafts are sterilized using gamma radiation according to the IAEA Code of Practice for the radiation sterilization of tissues allografts. The amount of grafts produced by the ITBBR from 2007 to 2018 were 120,800 cc of bone chips, 45,420 cm2 of amniotic membranes, 277 vials of de-mineralized bone granules (DMB), 95 pieces of massive bones, and 134 pieces of cranial bones. Overall, 112,748 cc of bone chips, 40,339 cm2 of amniotic membranes, 174 vials of DMB, 44 pieces of massive bones, and 64 pieces of cranial bones were transplanted successfully. Nevertheless, to cope up with the modern advanced concepts of cell and tissue banking for therapeutic purpose, ITBBR is working to set up facilities for skin banking, stem cells banking including amniotic and cord blood derived stem cells and scaffold designing. To ensure the quality, safety, ethical and regulatory issues are sustainable in cell and tissue banking practices, ITBBR always works with the Government of Bangladesh for enhancing the national tissue transplantation programme within the contemporary facilities.

Amnion and collagen-based blended hydrogel improves burn healing efficacy on a rat skin wound model in the presence of wound dressing biomembrane.

BACKGROUND: A burn wound is one of the most frequent and devastating injuries for patients which requires extensive care. Early treatment of burn wounds improves healing significantly. OBJECTIVE: This study was designed to investigate the efficacy of amnion and collagen-based hydrogels on cutaneous burn wound healing in rats with covering membrane. METHODS: We prepared a novel cell free hydrogel comprising human amnion, rabbit collagen, carboxymethyl cellulose sodium salt, citric acid, methyl paraben, propyl paraben, glycerin and triethanol amine. The wound covering membrane was developed from rabbit collagen and prawn shell chitosan. Beside swelling ratio, water absorption, equilibrium water content, gel fraction and spreadability analysis, in vitro cytotoxicity and biocompatibility tests were performed for the formulated hydrogels. Following the skin irritation study, second-degree burns were created on the dorsal region of the rats and the gels were applied with/without covering membrane to study the wound contraction and re-epithelialization period. RESULTS: The formulated hydrogels were observed non-cytotoxic and compatible with human blood cells. No erythema and edema were found in skin irritation assay confirming the safety and applicability. Hydrogel consisting in a combination of amnion and collagen demonstrated significantly rapid wound healing, driven by complete re-epithelialization (16.75 ± 0.96 days) and closure by wound contraction (72 ± 3.27%, P < 0.0000009) when wound dressing membrane was used, whereas this gel alone healed about 62.5 ± 4.43% (P < 0.00001) and required 18.75 ± 0.50 days to complete re-epithelialization. Additionally, the gel with covering membrane treated group had maximum average body weight, food and water intake. CONCLUSION: The amnion and collagen-based blended gel offers alternative possibilities to treat skin wounds when covered with film, which could overcome the limitations associated with modern therapeutic products such as high costs, long manufacturing times, complexities, storing, and presence of living biomaterials.

The FGF, TGFß and WNT axis Modulate Self-renewal of Human SIX2+ Urine Derived Renal Progenitor Cells.

Human urine is a non-invasive source of renal stem cells with regeneration potential. Urine-derived renal progenitor cells were isolated from 10 individuals of both genders and distinct ages. These renal progenitors express pluripotency-associated proteins- TRA-1-60, TRA-1-81, SSEA4, C-KIT and CD133, as well as the renal stem cell markers -SIX2, CITED1, WT1, CD24 and CD106. The transcriptomes of all SIX2+ renal progenitors clustered together, and distinct from the human kidney biopsy-derived epithelial proximal cells (hREPCs). Stimulation of the urine-derived renal progenitor cells (UdRPCs) with the GSK3ß-inhibitor (CHIR99021) induced differentiation. Transcriptome and KEGG pathway analysis revealed upregulation of WNT-associated genes- AXIN2, JUN and NKD1. Protein interaction network identified JUN- a downstream target of the WNT pathway in association with STAT3, ATF2 and MAPK1 as a putative negative regulator of self-renewal. Furthermore, like pluripotent stem cells, self-renewal is maintained by FGF2-driven TGFß-SMAD2/3 pathway. The urine-derived renal progenitor cells and the data presented should lay the foundation for studying nephrogenesis in human.

Human iPSC-derived iMSCs improve bone regeneration in mini-pigs.

Autologous bone marrow concentrate (BMC) and mesenchymal stem cells (MSCs) have beneficial effects on the healing of bone defects. To address the shortcomings associated with the use of primary MSCs, induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) have been proposed as an alternative. The aim of this study was to investigate the bone regeneration potential of human iMSCs combined with calcium phosphate granules (CPG) in critical-size defects in the proximal tibias of mini-pigs in the early phase of bone healing compared to that of a previously reported autograft treatment and treatment with a composite made of either a combination of autologous BMC and CPG or CPG alone. iMSCs were derived from iPSCs originating from human fetal foreskin fibroblasts (HFFs). They were able to differentiate into osteoblasts in vitro, express a plethora of bone morphogenic proteins (BMPs) and secrete paracrine signaling-associated cytokines such as PDGF-AA and osteopontin. Radiologically and histomorphometrically, HFF-iMSC + CPG transplantation resulted in significantly better osseous consolidation than the transplantation of CPG alone and produced no significantly different outcomes compared to the transplantation of autologous BMC + CPG after 6 weeks. The results of this translational study imply that iMSCs represent a valuable future treatment option for load-bearing bone defects in humans.

Characterization of burn wound healing gel prepared from human amniotic membrane and Aloe vera extract.

BACKGROUND: Skin burn wound is a notable medical burden worldwide. Rapid and effective treatment of burnt skin is vital to fasten wound closure and healing properly. Amniotic graft and Aloe vera are widely used as wound managing biomaterials. Sophisticated processing, high cost, availability, and the requirement of medics for transplantation limit the application of amnion grafts. We aim to prepare a novel gel from amnion combined with the Aloe vera extract for burn wound healing which overcome the limitations of graft. METHODS: Two percent human amniotic membrane (AM), Aloe vera (AV) and AM+AV gels were prepared. In vitro cytotoxicity, biocompatibility, cell attachment, proliferation, wound healing scratch assays were performed in presence of the distinct gels. After skin irritation study, second-degree burns were induced on dorsal region of Wistar rats; and gels were applied to observe the healing potential in vivo. Besides, macroscopical measurement of wound contraction and re-epithelialization; gel treated skin was histologically investigated by Hematoxylin and eosin (H&E) staining. Finally, quantitative assessment of angiogenesis, inflammation, and epithelialization was done. RESULTS: The gels were tested to be non-cytotoxic to nauplii and compatible with human blood and skin cells. Media containing 500 µg/mL AM+AV gel were observed to promote HaCaT and HFF1 cells attachment and proliferation. In vitro scratch assay demonstrated that AM+AV significantly accelerated wound closure through migration of HaCaT cells. No erythema and edema were observed in skin irritation experiments confirming the applicability of the gels. AV and AM+AV groups showed significantly accelerated wound closure through re-epithelialization and wound contraction with P < 0.01. Macroscopically, AM and AM+AV treated wound recovery rates were 87 and 90% respectively with P < 0.05. Histology analysis revealed significant epitheliazation and angiogenesis in AM+AV treated rats compared to control (P < 0.05). AM+AV treated wounds had thicker regenerated epidermis, increased number of blood vessels, and greater number of proliferating keratinocytes within the epidermis. CONCLUSION: We demonstrated that a gel consisting of a combination of amnion and Aloe vera extract has high efficacy as a burn wound healing product. Amniotic membrane combined with the carrier Aloe vera in gel format is easy to produce and to apply.

Human tissue banking in Bangladesh: hope for the patients of massive burns, surgical wound and bone associated complications.

Each year throughout Bangladesh, thousands of people suffering from massive burns and surgical wounds require amniotic grafts for transplantation. Additionally, the stricken persons of the country have to embrace bone associated disability for the whole life due to traumatic complications need bone graft to treat. As a result, these two problems are the largest financial burden as this situation not only affect the family of patients but also cripple down national economy. However, institute of tissue banking in Bangladesh has undertaken the service program on the processing, preservation and clinical applications of amnion membrane and bone graft for rehabilitative surgery. Importantly, in recent years, this institute has started cranial bone autograft processing and transplantation. In accidental cases such as head injury, it is difficult to provide suitable cranial bone allograft according to demand. In this situation, injured cranial bone of the patient is being transported to the lab of the institute, where the scientist, tissue banker and medic work together immediately to process the cranial bone and sterilize by gamma radiation; and after quality assurance, the processed cranial bone autograft is being supplied for replacement surgery. The use of irradiated amnion and bone allografts and cranial bone autograft in reconstructive surgery restore normalcy to lives of many patients from disabilities. This tissue bank is based on finding and obtaining qualified donors from the community and a demand for tissue grafts from the hospitals. Although growing needs for tissue transplantation but raw and processed tissue grafts preservation and banking braces enormous logistical limitations. The only human tissue bank in Bangladesh, however, ensures the availability of tissue allografts of high quality and acceptability to the recipients for rehabilitative surgery for a decade, regardless patients' socio-economic status.

Fabrication of biocompatible porous scaffolds based on hydroxyapatite/collagen/chitosan composite for restoration of defected maxillofacial mandible bone.

Fabrication of scaffolds from biomaterials for restoration of defected mandible bone has attained increased attention due to limited accessibility of natural bone for grafting. Hydroxyapatite (Ha), collagen type 1 (Col1) and chitosan (Cs) are widely used biomaterials which could be fabricated as a scaffold to overcome the paucity of bone substitutes. Here, rabbit Col1, shrimp Cs and bovine Ha were extracted and characterized with respect to physicochemical properties. Following the biocompatibility, degradability and cytotoxicity tests for Ha, Col1 and Cs a hydroxyapatite/collagen/chitosan (Ha·Col1·Cs) scaffold was fabricated using thermally induced phase separation technique. This scaffold was cross-linked with (1) either glutaraldehyde (GTA), (2) de-hydrothermal treatment (DTH), (3) irradiation (IR) and (4) 2-hydroxyethyl methacrylate (HEMA), resulting in four independent types (Ha·Col1·Cs-GTA, Ha·Col1·Cs-IR, Ha·Col1·Cs-DTH and Ha·Col1·Cs-HEMA). The developed composite scaffolds were porous with 3D interconnected fiber microstructure. However, Ha·Col1·Cs-IR and Ha·Col1·Cs-GTA showed better hydrophilicity and biodegradability. All four scaffolds showed desirable blood biocompatibility without cytotoxicity for brine shrimp. In vitro studies in the presence of human amniotic fluid-derived mesenchymal stem cells revealed that Ha·Col1·Cs-IR and Ha·Col1·Cs-DHT scaffolds were non-cytotoxic and compatible for cell attachment, growth and mineralization. Further, grafting of Ha·Col1·Cs-IR and Ha·Col1·Cs-DHT was performed in a surgically created non-load-bearing rabbit maxillofacial mandible defect model. Histological and radiological observations indicated the restoration of defected bone. Ha·Col1·Cs-IR and Ha·Col1·Cs-DHT could be used as an alternative treatment in bone defects and may contribute to further development of scaffolds for bone tissue engineering.

Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature.

BACKGROUND: Primary mesenchymal stem cells (MSCs) are fraught with aging-related shortfalls. Human-induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these aging-associated drawbacks. To date, the extent of the retention of aging-hallmarks in iMSCs differentiated from iPSCs derived from elderly donors remains unclear. METHODS: Fetal femur-derived MSCs (fMSCs) and adult bone marrow MSCs (aMSCs) were isolated, corresponding iPSCs were generated, and iMSCs were differentiated from fMSC-iPSCs, from aMSC-iPSCs, and from human embryonic stem cells (ESCs) H1. In addition, typical MSC characterization such as cell surface marker expression, differentiation capacity, secretome profile, and trancriptome analysis were conducted for the three distinct iMSC preparations-fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs. To verify these results, previously published data sets were used, and also, additional aMSCs and iMSCs were analyzed. RESULTS: fMSCs and aMSCs both express the typical MSC cell surface markers and can be differentiated into osteogenic, adipogenic, and chondrogenic lineages in vitro. However, the transcriptome analysis revealed overlapping and distinct gene expression patterns and showed that fMSCs express more genes in common with ESCs than with aMSCs. fMSC-iMSCs, aMSC-iMSCs, and ESC-iMSCs met the criteria set out for MSCs. Dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and separated from the MSC-iPSCs and ESCs. iMSCs irrespective of donor age and cell type acquired a rejuvenation-associated gene signature, specifically, the expression of INHBE, DNMT3B, POU5F1P1, CDKN1C, and GCNT2 which are also expressed in pluripotent stem cells (iPSCs and ESC) but not in the parental aMSCs. iMSCs expressed more genes in common with fMSCs than with aMSCs. Independent real-time PCR comparing aMSCs, fMSCs, and iMSCs confirmed the differential expression of the rejuvenation (COX7A, EZA2, and TMEM119) and aging (CXADR and IGSF3) signatures. Importantly, in terms of regenerative medicine, iMSCs acquired a secretome (e.g., angiogenin, DKK-1, IL-8, PDGF-AA, osteopontin, SERPINE1, and VEGF) similar to that of fMSCs and aMSCs, thus highlighting their ability to act via paracrine signaling. CONCLUSIONS: iMSCs irrespective of donor age and cell source acquire a rejuvenation gene signature. The iMSC concept could allow circumventing the drawbacks associated with the use of adult MSCs und thus provide a promising tool for use in various clinical settings in the future.

The presence of human mesenchymal stem cells of renal origin in amniotic fluid increases with gestational time.

BACKGROUND: Established therapies for managing kidney dysfunction such as kidney dialysis and transplantation are limited due to the shortage of compatible donated organs and high costs. Stem cell-based therapies are currently under investigation as an alternative treatment option. As amniotic fluid is composed of fetal urine harboring mesenchymal stem cells (AF-MSCs), we hypothesized that third-trimester amniotic fluid could be a novel source of renal progenitor and differentiated cells. METHODS: Human third-trimester amniotic fluid cells (AFCs) were isolated and cultured in distinct media. These cells were characterized as renal progenitor cells with respect to cell morphology, cell surface marker expression, transcriptome and differentiation into chondrocytes, osteoblasts and adipocytes. To test for renal function, a comparative albumin endocytosis assay was performed using AF-MSCs and commercially available renal cells derived from kidney biopsies. Comparative transcriptome analyses of first, second and third trimester-derived AF-MSCs were conducted to monitor expression of renal-related genes. RESULTS: Regardless of the media used, AFCs showed expression of pluripotency-associated markers such as SSEA4, TRA-1-60, TRA-1-81 and C-Kit. They also express the mesenchymal marker Vimentin. Immunophenotyping confirmed that third-trimester AFCs are bona fide MSCs. AF-MSCs expressed the master renal progenitor markers SIX2 and CITED1, in addition to typical renal proteins such as PODXL, LHX1, BRN1 and PAX8. Albumin endocytosis assays demonstrated the functionality of AF-MSCs as renal cells. Additionally, upregulated expression of BMP7 and downregulation of WT1, CD133, SIX2 and C-Kit were observed upon activation of WNT signaling by treatment with the GSK-3 inhibitor CHIR99201. Transcriptome analysis and semiquantitative PCR revealed increasing expression levels of renal-specific genes (e.g., SALL1, HNF4B, SIX2) with gestational time. Moreover, AF-MSCs shared more genes with human kidney cells than with native MSCs and gene ontology terms revealed involvement of biological processes associated with kidney morphogenesis. CONCLUSIONS: Third-trimester amniotic fluid contains AF-MSCs of renal origin and this novel source of kidney progenitors may have enormous future potentials for disease modeling, renal repair and drug screening.

Isolation and Molecular Characterization of Amniotic Fluid-Derived Mesenchymal Stem Cells Obtained from Caesarean Sections.

Human amniotic fluid cells are immune-privileged with low immunogenicity and anti-inflammatory properties. They are able to self-renew, are highly proliferative, and have a broad differentiation potential, making them amenable for cell-based therapies. Amniotic fluid (AF) is routinely obtained via amniocentesis and contains heterogeneous populations of foetal-derived progenitor cells including mesenchymal stem cells (MSCs). In this study, we isolated human MSCs from AF (AF-MSCs) obtained during Caesarean sections (C-sections) and characterized them. These AF-MSCs showed typical MSC characteristics such as morphology, in vitro differentiation potential, surface marker expression, and secreted factors. Besides vimentin and the stem cell marker CD133, subpopulations of AF-MSCs expressed pluripotency-associated markers such as SSEA4, c-Kit, TRA-1-60, and TRA-1-81. The secretome and related gene ontology (GO) terms underline their immune modulatory properties. Furthermore, transcriptome analyses revealed similarities with native foetal bone marrow-derived MSCs. Significant KEGG pathways as well as GO terms are mostly related to immune function, embryonic skeletal system, and TGFß-signalling. An AF-MSC-enriched gene set included putative AF-MSC markers PSG5, EMX-2, and EVR-3. In essence, C-section-derived AF-MSCs can be routinely obtained and are amenable for personalized cell therapies and disease modelling.

Tissue banking in Bangladesh: 12 years of experience (2003-2014).

Tissue Banking and Biomaterial Research Unit (TBBRU), the only tissue bank of Bangladesh, has been established to create an available supply of human tissue allografts for transplantation in Bangladesh. Since its establishment in 2003, TBBRU strictly follows the guidelines of tissue banking setup by the International Atomic Energy Agency, the European Association of Tissue Banks and the American Association of Tissue Banks. Though started serving from earlier, regular supply of tissue allografts from this bank were documented at the end of 2006. From January 2007 to December 2014, 3747 bones and 5772 amniotic sacs were collected from live tissue donors. During this period, 59,489 cc bone allografts and 23,472 pieces of amniotic membrane allografts were processed. In the same period, 58,483 cc bone allografts and 20,786 pieces membrane were supplied to different hospitals throughout the country on the basis of demand. The outcomes of the concerted efforts of tissue banking professionals and physicians were the restoration of health and hope of 3662 patients during the last 8 years.

TGF-ß/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation.

Transforming growth factor-beta (TGF-ß)/bone morphogenetic protein (BMP) plays a fundamental role in the regulation of bone organogenesis through the activation of receptor serine/threonine kinases. Perturbations of TGF-ß/BMP activity are almost invariably linked to a wide variety of clinical outcomes, i.e., skeletal, extra skeletal anomalies, autoimmune, cancer, and cardiovascular diseases. Phosphorylation of TGF-ß (I/II) or BMP receptors activates intracellular downstream Smads, the transducer of TGF-ß/BMP signals. This signaling is modulated by various factors and pathways, including transcription factor Runx2. The signaling network in skeletal development and bone formation is overwhelmingly complex and highly time and space specific. Additive, positive, negative, or synergistic effects are observed when TGF-ß/BMP interacts with the pathways of MAPK, Wnt, Hedgehog (Hh), Notch, Akt/mTOR, and miRNA to regulate the effects of BMP-induced signaling in bone dynamics. Accumulating evidence indicates that Runx2 is the key integrator, whereas Hh is a possible modulator, miRNAs are regulators, and ß-catenin is a mediator/regulator within the extensive intracellular network. This review focuses on the activation of BMP signaling and interaction with other regulatory components and pathways highlighting the molecular mechanisms regarding TGF-ß/BMP function and regulation that could allow understanding the complexity of bone tissue dynamics.

Psychological stress and aging: role of glucocorticoids (GCs).

Psychological stress has extreme adverse consequences on health. However, the molecular mechanisms that mediate and accelerate the process of aging due to stress hormone are not well defined. This review has focused on diverse molecular paths that come out in response to chronic psychological stress via releasing of excessive glucocorticoids (GCs), involved in the aging process. GCs suppress transcription of nuclear cell adhesion molecules which impair synaptic plasticity, memory formation, and cognitive ability. Again, GCs promote muscle atrophy by means of motivating ubiquitin proteasome system and can repress muscle protein synthesis by inhibition of PI3-kinase/Akt pathway. GCs also inhibit interleukin-2 synthesis through suppressing T cell receptor signal that leads to loss of T cell activation, proliferation, and B-cell activation. Moreover, GCs increase the expression of collagenase-3, RANK ligand, and colony stimulating factor-1 that induce bone resorption. In general, stress-induced GCs can play causal role for aging and age-related disorders.