scholarly journals Regulation of Hedgehog signaling Offers A Novel Perspective for Bone Homeostasis Disorder Treatment

2019 ◽  
Vol 20 (16) ◽  
pp. 3981 ◽  
Author(s):  
Wen-Ting Lv ◽  
Dong-Hua Du ◽  
Rui-Juan Gao ◽  
Chun-Wei Yu ◽  
Yan Jia ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Bone Development ◽  
Therapeutic Option ◽  
Bone Homeostasis ◽  
Rankl Expression ◽  
Activated T Cells ◽  
Parathyroid Hormone Related Protein ◽  
Element Binding Protein ◽  
Pthrp Expression ◽  
Hh Signaling

The hedgehog (HH) signaling pathway is central to the regulation of bone development and homeostasis. HH signaling is not only involved in osteoblast differentiation from bone marrow mesenchymal stem cells (BM-MSCs), but also acts upstream within osteoblasts via the OPG/RANK/RANKL axis to control the expression of RANKL. HH signaling has been found to up-regulate parathyroid hormone related protein (PTHrP) expression in osteoblasts, which in turn activates its downstream targets nuclear factor of activated T cells (NFAT) and cAMP responsive element binding protein (CREB), and as a result CREB and NFAT cooperatively increase RANKL expression and osteoclastogenesis. Osteoblasts must remain in balance with osteoclasts in order to avoid excessive bone formation or resorption, thereby maintaining bone homeostasis. This review systemically summarizes the mechanisms whereby HH signaling induces osteoblast development and controls RANKL expression through PTHrP in osteoblasts. Proper targeting of HH signaling may offer a therapeutic option for treating bone homeostasis disorders.

scholarly journals Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Zeeshan Javed ◽  
Muhammad Javed Iqbal ◽  
Amna Rasheed ◽  
Haleema Sadia ◽  
Shahid Raza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Molecules ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Therapeutic Option ◽  
High Specificity ◽  
Alternative Drug ◽  
Delivery Platform ◽  
Hh Signaling ◽  
Differentiation And Proliferation

Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.

scholarly journals Hedgehog Signaling in Skeletal Development: Roles of Indian Hedgehog and the Mode of Its Action

2020 ◽  
Vol 21 (18) ◽  
pp. 6665 ◽  
Author(s):  
Shinsuke Ohba
Keyword(s):  
Hedgehog Signaling ◽  
Feedback Loop ◽  
Skeletal Development ◽  
Indian Hedgehog ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Genetic Studies ◽  
Parathyroid Hormone Related Protein ◽  
Gli Transcription Factors ◽  
Hh Signaling

Hedgehog (Hh) signaling is highly conserved among species and plays indispensable roles in various developmental processes. There are three Hh members in mammals; one of them, Indian hedgehog (Ihh), is expressed in prehypertrophic and hypertrophic chondrocytes during endochondral ossification. Based on mouse genetic studies, three major functions of Ihh have been proposed: (1) Regulation of chondrocyte differentiation via a negative feedback loop formed together with parathyroid hormone-related protein (PTHrP), (2) promotion of chondrocyte proliferation, and (3) specification of bone-forming osteoblasts. Gli transcription factors mediate the major aspect of Hh signaling in this context. Gli3 has dominant roles in the growth plate chondrocytes, whereas Gli1, Gli2, and Gli3 collectively mediate biological functions of Hh signaling in osteoblast specification. Recent studies have also highlighted postnatal roles of the signaling in maintenance and repair of skeletal tissues.

TGF-β promotion of GLI2 induced pthrp expression is independent of canonical hedgehog signaling

Bone ◽  
2011 ◽  
Vol 48 (1) ◽  
pp. S14-S15 ◽  
Author(s):  
R.W. Johnson* ◽  
M.P. Nguyen ◽  
S. Padalecki ◽  
B. Grubbs ◽  
A.R. Merkel ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Pthrp Expression

scholarly journals The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Ming Ji ◽  
Zhihui Zhang ◽  
Songwen Lin ◽  
Chunyang Wang ◽  
Jing Jin ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Hedgehog Signaling Pathway ◽  
Orthotopic Mouse Model ◽  
Cycle Arrest ◽  
The Central Nervous System

Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.

scholarly journals Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

Development ◽  
2021 ◽  
Vol 148 (19) ◽  
Author(s):  
Jennifer H. Kong ◽  
Cullen B. Young ◽  
Ganesh V. Pusapati ◽  
F. Hernán Espinoza ◽  
Chandni B. Patel ◽  
...  
Keyword(s):  
Small Molecules ◽  
Birth Defects ◽  
Birth Defect ◽  
Hedgehog Signaling ◽  
Multiple Birth ◽  
In Utero Exposure ◽  
Membrane Protein Complex ◽  
Protein Target ◽  
Hh Signaling ◽  
Genetic And Environmental Factors

ABSTRACT Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo−/− embryos. Additionally, tissues that develop normally in Mosmo−/− embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

scholarly journals Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yi Wang ◽  
Xu Zhang ◽  
Huihui Huang ◽  
Yin Xia ◽  
YiFei Yao ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Hedgehog Signaling ◽  
Progenitor Cell ◽  
Tendon Repair ◽  
Tendon Sheath ◽  
Lineage Tracing ◽  
Specific Marker ◽  
Molecular Function ◽  
Hh Signaling ◽  
Necessary And Sufficient

Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.

Role of knot (kn) in Wing Patterning in Drosophila

Genetics ◽  
1997 ◽  
Vol 147 (3) ◽  
pp. 1203-1212 ◽  
Author(s):  
Katerina Nestoras ◽  
Helena Lee ◽  
Jym Mohler
Keyword(s):  
Hedgehog Signaling ◽  
Imaginal Disc ◽  
Hedgehog Signaling Pathway ◽  
Posterior Compartment ◽  
Drosophila Wing ◽  
Compartment Boundary ◽  
Hh Signaling ◽  
Embryonic Segmentation ◽  
Anterior Posterior

We have undertaken a genetic analysis of new strong alleles of knot (kn). The original kn1 mutation causes an alteration of wing patterning similar to that associated with mutations of fused (fu), an apparent fusion of veins 3 and 4 in the wing. However, unlike fu, strong kn mutations do not affect embryonic segmentation and indicate that kn is not a component of a general Hh (Hedgehog)-signaling pathway. Instead we find that kn has a specific role in those cells of the wing imaginal disc that are subject to ptc-mediated Hh-signaling. Our results suggest a model for patterning the medial portion of the Drosophila wing, whereby the separation of veins 3 and 4 is maintained by kn activation in the intervening region in response to Hh-signaling across the adjacent anterior-posterior compartment boundary.

BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation

Development ◽  
2001 ◽  
Vol 128 (22) ◽  
pp. 4523-4534 ◽  
Author(s):  
Eleonora Minina ◽  
Hans Markus Wenzel ◽  
Conny Kreschel ◽  
Seth Karp ◽  
William Gaffield ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Feedback Loop ◽  
Bmp Signaling ◽  
Signaling Systems ◽  
Chondrocyte Maturation ◽  
Parathyroid Hormone Related Protein ◽  
Proliferation And Differentiation ◽  
Mouse Limb ◽  
Pthrp Expression

During endochondral ossification, two secreted signals, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP), have been shown to form a negative feedback loop regulating the onset of hypertrophic differentiation of chondrocytes. Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop. To analyze the relationship between the two signaling pathways, we used an organ culture system for limb explants of mouse and chick embryos. We manipulated chondrocyte differentiation by supplementing these cultures either with BMP2, PTHrP and Sonic hedgehog as activators or with Noggin and cyclopamine as inhibitors of the BMP and Ihh/PTHrP signaling systems. Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation. Noggin treatment of limbs from these mice did not antagonize the effects of Ihh overexpression. Conversely, the promotion of chondrocyte maturation induced by cyclopamine, which blocks Ihh signaling, could not be rescued with BMP2. Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation. Similar results were obtained using cultures of chick limbs. We further investigated the role of BMP signaling in regulating proliferation and hypertrophic differentiation of chondrocytes and identified three functions of BMP signaling in this process. First we found that maintaining a normal proliferation rate requires BMP and Ihh signaling acting in parallel. We further identified a role for BMP signaling in modulating the expression of Ihh. Finally, the application of Noggin to mouse limb explants resulted in advanced differentiation of terminally hypertrophic cells, implicating BMP signaling in delaying the process of hypertrophic differentiation itself. This role of BMP signaling is independent of the Ihh/PTHrP pathway.

scholarly journals Impact of the Autonomic Nervous System on the Skeleton

2018 ◽  
Vol 98 (3) ◽  
pp. 1083-1112 ◽  
Author(s):  
Florent Elefteriou
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Cancer Metastasis ◽  
Bone Development ◽  
Autonomic Nerves ◽  
Bone Homeostasis ◽  
Bone Mass Accrual ◽  
The Central Nervous System

It is from the discovery of leptin and the central nervous system as a regulator of bone remodeling that the presence of autonomic nerves within the skeleton transitioned from a mere histological observation to the mechanism whereby neurons of the central nervous system communicate with cells of the bone microenvironment and regulate bone homeostasis. This shift in paradigm sparked new preclinical and clinical investigations aimed at defining the contribution of sympathetic, parasympathetic, and sensory nerves to the process of bone development, bone mass accrual, bone remodeling, and cancer metastasis. The aim of this article is to review the data that led to the current understanding of the interactions between the autonomic and skeletal systems and to present a critical appraisal of the literature, bringing forth a schema that can put into physiological and clinical context the main genetic and pharmacological observations pointing to the existence of an autonomic control of skeletal homeostasis. The different types of nerves found in the skeleton, their functional interactions with bone cells, their impact on bone development, bone mass accrual and remodeling, and the possible clinical or pathophysiological relevance of these findings are discussed.

scholarly journals Ectopic Hedgehog Signaling Causes Cleft Palate and Defective Osteogenesis

2018 ◽  
Vol 97 (13) ◽  
pp. 1485-1493 ◽  
Author(s):  
N.L. Hammond ◽  
K.J. Brookes ◽  
M.J. Dixon
Keyword(s):  
Cleft Palate ◽  
Hedgehog Signaling ◽  
Regulatory Networks ◽  
Neural Crest Cell ◽  
Bmp Signaling ◽  
The Novel ◽  
Morphogenetic Protein ◽  
Secondary Palate ◽  
Hh Signaling ◽  
Crest Cell

Cleft palate is a common birth defect that frequently occurs in human congenital malformations caused by mutations in components of the Sonic Hedgehog (S HH) signaling cascade. Shh is expressed in dynamic, spatiotemporal domains within epithelial rugae and plays a key role in driving epithelial-mesenchymal interactions that are central to development of the secondary palate. However, the gene regulatory networks downstream of Hedgehog (Hh) signaling are incompletely characterized. Here, we show that ectopic Hh signaling in the palatal mesenchyme disrupts oral-nasal patterning of the neural crest cell–derived ectomesenchyme of the palatal shelves, leading to defective palatine bone formation and fully penetrant cleft palate. We show that a series of Fox transcription factors, including the novel direct target Foxl1, function downstream of Hh signaling in the secondary palate. Furthermore, we demonstrate that Wnt/bone morphogenetic protein (BMP) antagonists, in particular Sostdc1, are positively regulated by Hh signaling, concomitant with downregulation of key regulators of osteogenesis and BMP signaling effectors. Our data demonstrate that ectopic Hh-Smo signaling downregulates Wnt/BMP pathways, at least in part by upregulating Sostdc1, resulting in cleft palate and defective osteogenesis.

Sign in / Sign up

Export Citation Format

Share Document