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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
During embryonic growth, neural precursor cells generated in the rhombic lip of the dorsal hindbrain migrate along the surface of the cerebellum to form the external granule layer (EGL). The secretion of bone morphogenic proteins (BMPs), such as BMP6, BMP7, and GDF7, encourages further proliferation generating a rich pool of granule cell precursors (GCPs) in the developing EGL [20, 36]. As older cells exit the EGL and migrate through a layer of Purkinje cells, they encounter the Hedgehog pathway ligand, Sonic hedgehog (SHH), a highly conserved embryonic signaling system which binds to its receptor, Patched 1 (PTCH1), expressed on GCPs in the EGL [37, 38]. Downstream effectors include the GLI family of transcription factors (GLI1, GLI2, and GLI3), which activate transcription of genes, such as cyclinD1 (CCND1) and MYC, thereby facilitating GCP proliferation and migration [7, 20, 36, 39]. After post-natal cerebellar development, this pathway goes dormant with the 12-pass transmembrane receptor, PTCH1, keeping the 7-pass transmembrane protein, Smoothened (SMO), in an inactivated state [40]. This, in turn, leads to the sequestration of downstream effectors of the SHH pathway by Suppressor-of-Fused (SUFU), effectively silencing gene expression [7]. Deregulated binding of SHH to PTCH1 releases and constitutively activates SMO which, in turn, inhibits SUFU, leading to release and nuclear translocation of GLI1-3; as a result, aberrant gene transcription is activated, facilitating phenotypic transformation into medulloblastoma [7].
Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
It has been shown that hypertrophy follows chondrocytes switching from aerobic to anaerobic respiration. Evidence for this is provided by examining creatine kinase, an enzyme that catalyzes the formation of ATP in tissues under oxygen stress. Creatine kinase activity is related to both chondrocyte maturation and hypertrophy, and the activity of this enzyme increases to prepare for a hypoxic state (Shapiro et al. 1992). Growth factors that have been shown to affect hypertrophy include the BMPs and TGF-β. BMP2, 4, 6, and 7 have all been implicated in chondrocyte hypertrophy. Of these, BMP6 and 7 are expressed in hypertrophic chondrocytes (Gitelman et al. 1994; Houston et al. 1994), and the exogenous addition of BMP2 and 4 results in increases in chondrocyte hypertrophy (De Luca et al. 2001; Shum et al. 2003). BMP-induced bone formation can occur without cartilage formation, leading to their use for bone repair and tissue engineering (Sasano et al. 1993; Reddi 1998b). Regulation of hypertrophy by BMP also seems to involve GDF5, as overexpression of GDF5 results in enhanced chondrocyte maturation and hypertrophy (Coleman and Tuan 2003a,b).
Injectable Scaffolds for Oral Tissue Regeneration
Published in Vincenzo Guarino, Marco Antonio Alvarez-Pérez, Current Advances in Oral and Craniofacial Tissue Engineering, 2020
J.L. Suárez-Franco, B.I. Cerda-Cristerna
Injectable scaffolds have been already tested on in vivo models. Regenerative periodontal therapy has been studied for many decades, thus animal models for periodontal regeneration have been usually used for years. The hydrogels have been applied in rats or dogs. Some examples are described next. A ChBIS prepared withß-glycerophosphate (GC) (Ch/GC 9:1) was used to grow human periodontal ligament cells (HPDLCs) in an in vivo model in a canine model of periodontal regeneration to evaluate furcal healing. The scaffold was injected in the furcation area, and after 12 weeks of treatment, an 80% increase in bone was observed, with osteoblasts, cell-like newly formed cementum and newly regenerated periodontal ligament were observed at histological examination (Zang et al. 2014). A ChBIS loaded with bone morphogenetic protein 6 (BA/1P 6) also showed bone formation. The injectable scaffold was thermosensitive, it was a fluid at 4°C and was in a semi-solid phase once it was injected in an 37°C environment. The injectable scaffold was tested in a periodontal defect model in rats for 6 weeks. Micro-CT analysis showed that the treated defects developed bone regeneration with a significant bone volume and bone bridging and trabecular bone. Histological analysis demonstrated formation of a new bone, of cementum, connective tissue and of periodontal ligament (Chien et al. 2018). Gelatin-based Injectable Scaffolds (GbIS) have shown induction of bone repairing. A hydrogel based on gelatin with PLGA microspheres loaded with simvastatin promoted bone formation in rats (Li et al. 2019). The simvastatin promoted bone regeneration associated with the ability of statins to induce bone morphogenetic protein 2 gene expression in osteoblast and marrow cells, its release from the microspheres in the GbIS promotes bone formation (Li et al. 2019). The GbIS injected in sockets in mandible of rats after tooth extraction increased bone mineral density that grew significantly from 1 week to 8 weeks, both radiographical and histological examinations demonstrated the bone formation (Li et al. 2019).
Immunologic underpinnings and treatment of morphea
Published in Expert Review of Clinical Immunology, 2022
Avery H. LaChance, Nathaniel Goldman, Bina Kassamali, Ruth Ann Vleugels
Another cytokine within the TGF-β superfamily that may play a role in the pathogenesis of morphea is bone morphogenetic protein-6 (BMP6). Cultured fibroblasts taken from skin biopsies in patients with morphea express significantly elevated mRNA levels of BMP6 when compared to fibroblasts derived from neonatal or adult healthy skin biopsies [77]. Additionally, BMP6 stained positive in all biopsies taken from morphea plaques but from none of the biopsies taken from normal skin [77]. BMP6 mRNA levels are also significantly elevated in fibroblasts cultured from later stage fibrotic morphea plaques when compared with early inflammatory stage plaques. However, rather than contributing to fibrosis in morphea, the study postulates that BMP6 expression may occur as a reactive/protective response to the development of fibrosis in morphea [77]. These results prompted the authors to propose that BMP6 should be explored further as a potential therapeutic target for patients with morphea and other cutaneous sclerosing disorders [77].
Differential expression of BMP/SMAD signaling and ovarian-associated genes in the granulosa cells of FecB introgressed GMM sheep
Published in Systems Biology in Reproductive Medicine, 2020
Satish Kumar, Pradeep Kumar Rajput, Sangharatna V. Bahire, Basanti Jyotsana, Vijay Kumar, Davendra Kumar
It is well known that the members of the TGFβ superfamily play an important role in the proliferation and differentiation of the somatic cells (GCs and theca cells) and germ cell (oocyte) and also provide intercellular communication between the GCs and the oocytes. Several BMP factors play an important role in the ovarian follicular development of mammalian species. Some BMP factors (viz. BMP2) induce bone and cartilage formation in mammals (Chen et al. 2004). While BMP4 regulates the formation of teeth, limbs, and bone from mesoderm, it also plays an important role in fracture repair, epidermis formation, dorsal-ventral axis formation, and ovarian follicle development. Further, BMP4, in conjunction with BMP7, also regulate an early ovarian follicle development and primordial-to-primary follicle transition (Nilsson and Skinner 2003). In a similar fashion, BMP6 plays a role in homeostatis, bone and cartilage formation, but also enhanced the growth of secondary follicles in goat (Frota et al. 2013).
Expression of serum BMP6 and hepcidin in cancer-related anemia
Published in Hematology, 2020
Zhen Cheng, Min Yan, Ye Lu, Xiang-Tao Pan
The BMP-SMAD signaling pathway regulates the self-renewal and differentiation of stem cells, and cell proliferation, migration, and apoptosis, as well as embryonic development and maintenance of postnatal tissue homeostasis. Many results have confirmed that BMP6 is the key regulator of hepcidin with the systemic iron load state as the initiating signal, which is secreted mainly by liver nonessential cells [26]. At present, most studies are about hepatic BMP6 and few studies on serum BMP6. We found that in the normal CRP group, the level of serum BMP6 in the anemia subgroup was higher than that in the non-anemia subgroup (P < 0.05), but the levels of CRP, hepcidin, and SF were not associated with anemia in this group. In addition, we further confirmed that the level of BMP6 was negatively correlated with Hb in the correlation analysis while showed no correlation with hepcidin. It was puzzling there is no dependence between BMP6 and hepcidin. Regrettably, we only detected the serum concentration and did not detect the expression in the tissue cells, so the relationship between the serum and heptic BMP6 cannot be clarified at present, which needs to be further studied. These results suggested BMP6 may be associated with anemia in tumor patients when CRP was normal, namely under non-inflammatory state, but the exact mechanism was unclear.