scholarly journals Subchondral Bone Remodeling: A Therapeutic Target for Osteoarthritis

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaobo Zhu ◽  
Yau Tsz Chan ◽  
Patrick S. H. Yung ◽  
Rocky S. Tuan ◽  
Yangzi Jiang
Keyword(s):  
Extracellular Matrix ◽  
Signaling Pathways ◽  
Bone Remodeling ◽  
Molecular Mechanism ◽  
Subchondral Bone ◽  
Therapeutic Target ◽  
Therapeutic Targets ◽  
Regenerative Therapies

There is emerging awareness that subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). This review presents recent investigations on the cellular and molecular mechanism of subchondral bone remodeling, and summarizes the current interventions and potential therapeutic targets related to OA subchondral bone remodeling. The first part of this review covers key cells and molecular mediators involved in subchondral bone remodeling (osteoclasts, osteoblasts, osteocytes, bone extracellular matrix, vascularization, nerve innervation, and related signaling pathways). The second part of this review describes candidate treatments for OA subchondral bone remodeling, including the use of bone-acting reagents and the application of regenerative therapies. Currently available clinical OA therapies and known responses in subchondral bone remodeling are summarized as a basis for the investigation of potential therapeutic mediators.

scholarly journals Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 927 ◽  
Author(s):  
Szu-Yu Chien ◽  
Chun-Hao Tsai ◽  
Shan-Chi Liu ◽  
Chien-Chung Huang ◽  
Tzu-Hung Lin ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Signaling Pathways ◽  
Bone Remodeling ◽  
Subchondral Bone ◽  
Bone Destruction ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Mitogen Activated Protein Kinase ◽  
Bone Morphogenetic Protein 2 ◽  
Joint Disease

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.

Diacylfuroxans Are Masked Nitrile Oxides That Inhibit GPX4 Covalently

2019 ◽  
Author(s):  
John Eaton ◽  
Richard A. Ruberto ◽  
Anneke Kramm ◽  
Vasanthi S. Viswanathan ◽  
Stuart Schreiber
Keyword(s):  
Molecular Mechanism ◽  
Mechanism Of Action ◽  
Therapeutic Target ◽  
Biologically Active ◽  
Drug Resistant ◽  
Nitrile Oxides ◽  
Molecular Mechanism Of Action

<div><div><div><p>GPX4 represents a promising yet difficult-to-drug therapeutic target for the treatment of, among others, drug-resistant cancers. While most GPX4 inhibitors rely on a chloroacetamide moiety to modify covalently the protein’s catalytic selenocysteine residue, the discovery and mechanistic elucidation of structurally diverse GPX4-inhibiting molecules has uncovered novel electrophilic warheads that bind and inhibit GPX4. Here we report our discovery that diacylfuroxans can act as masked nitrile oxides that inhibit GPX4 covalently. These observations illuminate a novel molecular mechanism of action for biologically active furoxans and also suggest that nitrile oxides may be uniquely suited to targeting GPX4.</p></div></div></div>

scholarly journals Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

2021 ◽  
Author(s):  
Nicole Bechmann ◽  
Graeme Eisenhofer
Keyword(s):  
Extracellular Matrix ◽  
Signaling Pathways ◽  
Metastatic Disease ◽  
Therapeutic Intervention ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Germline Mutations ◽  
Driver Mutations ◽  
Mesenchymal Transition ◽  
Therapeutic Relevance

AbstractGermline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6–6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention.

Early inhibition of subchondral bone remodeling slows load‐induced post‐traumatic osteoarthritis development in mice

2021 ◽  
Author(s):  
Sophia N. Ziemian ◽  
Ana Witkowski ◽  
Timothy M Wright ◽  
Miguel Otero ◽  
Marjolein C. H. Meulen
Keyword(s):  
Bone Remodeling ◽  
Subchondral Bone ◽  
Post Traumatic ◽  
Early Inhibition

scholarly journals Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target

2013 ◽  
Vol 110 (10) ◽  
pp. E928-E937 ◽  
Author(s):  
L. S. Verjee ◽  
J. S. N. Verhoekx ◽  
J. K. K. Chan ◽  
T. Krausgruber ◽  
V. Nicolaidou ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Therapeutic Target ◽  
Dupuytren’S Disease ◽  
Dupuytren's Disease

scholarly journals Signaling Mechanisms in the Regulation of Renal Matrix Metabolism in Diabetes

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Meenalakshmi M. Mariappan
Keyword(s):  
Extracellular Matrix ◽  
Signaling Pathways ◽  
Matrix Protein ◽  
Structural Changes ◽  
Mammalian Target Of Rapamycin ◽  
Adverse Outcomes ◽  
Matrix Proteins ◽  
Extracellular Matrix Protein ◽  
Renal Hypertrophy ◽  
Matrix Metabolism

Renal hypertrophy and accumulation of extracellular matrix proteins are among cardinal manifestations of diabetic nephropathy. TGF beta system has been implicated in the pathogenesis of these manifestations. Among signaling pathways activated in the kidney in diabetes, mTOR- (mammalian target of rapamycin-)regulated pathways are pivotal in orchestrating high glucose-induced production of ECM proteins leading to functional and structural changes in the kidney culminating in adverse outcomes. Understanding signaling pathways that influence individual matrix protein expression could lead to the development of new interventional strategies. This paper will highlight some of the diverse components of the signaling network stimulated by hyperglycemia with an emphasis on extracellular matrix protein metabolism in the kidney in diabetes.

Inositide-dependent signaling pathways as new therapeutic targets in myelodysplastic syndromes

2015 ◽  
Vol 20 (6) ◽  
pp. 677-687 ◽  
Author(s):  
Sara Mongiorgi ◽  
Carlo Finelli ◽  
Yong Ryoul Yang ◽  
Cristina Clissa ◽  
James A. McCubrey ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Myelodysplastic Syndromes ◽  
Therapeutic Targets ◽  
New Therapeutic Targets

Transcriptomic Analysis of MSTN Knockout in the Early Differentiation of Chicken Fetal Myoblasts

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 58
Author(s):  
Ke Xu ◽  
Hao Zhou ◽  
Chengxiao Han ◽  
Zhong Xu ◽  
Jinmei Ding ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanism ◽  
Growth And Development ◽  
Biological Effects ◽  
Muscle Growth ◽  
Negative Regulator ◽  
Myoblast Differentiation ◽  
Fatty Acid Binding ◽  
Knock Out ◽  
Early Differentiation

In mammals, Myostatin (MSTN) is a known negative regulator of muscle growth and development, but its role in birds is poorly understood. To investigate the molecular mechanism of MSTN on muscle growth and development in chickens, we knocked out MSTN in chicken fetal myoblasts (CFMs) and sequenced the mRNA transcriptomes. The amplicon sequencing results show that the editing efficiency of the cells was 76%. The transcriptomic results showed that 296 differentially expressed genes were generated after down-regulation of MSTN, including angiotensin I converting enzyme (ACE), extracellular fatty acid-binding protein (EXFABP) and troponin T1, slow skeletal type (TNNT1). These genes are closely associated with myoblast differentiation, muscle growth and energy metabolism. Subsequent enrichment analysis showed that DEGs of CFMs were related to MAPK, P13K/AKT, and STAT3 signaling pathways. The MAPK and P13K/AKT signaling pathways are two of the three known signaling pathways involved in the biological effects of MSTN in mammals, and the STAT3 pathway is also significantly enriched in MSTN knock out chicken leg muscles. The results of this study will help to understand the possible molecular mechanism of MSTN regulating the early differentiation of CFMs and lay a foundation for further research on the molecular mechanism of MSTN involvement in muscle growth and development.

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