Parathyroid hormone (PTH) and glycogen synthase kinase-3 (GSK-3) inhibitor 603281-31-8, administered once daily increased bone formation in vivo. We investigated the molecular mechanisms of the anabolic responses of PTH and 603281-31-8 in rat osteopenia model. Female 6-month-old rats were ovariectomized (Ovx) and permitted to lose bone for 1 month, followed by treatment with PTH (1-38) at 10 microg/kg/day s.c. or 603281-31-8 at 3 mg/kg/day p.o. for 60 days. Twenty-four hours after the last treatment, RNA from distal femur metaphysis was subjected to gene expression analysis. Differentially expressed genes (P<0.05) were subjected to pathway analysis to delineate relevant bio-processes involved in skeletal biology. Genes involved in morphogenesis, cell growth/differentiation, and apoptosis were significantly altered by Ovx and the treatments. Analysis of morphogenesis genes showed an overrepresentation of genes involved in osteogenesis, chondrogenesis, and adipogenesis. A striking finding was that Ovx decreased several markers of osteogenesis/chondrogenesis and increased markers of adipogenesis/lipid metabolism. Treatment with either PTH or the GSK-3 inhibitor reversed these effects, albeit at different levels. Histological analysis confirmed that osteopenia in Ovx animals was associated with three-fold increase in marrow adiposity. PTH and GSK-3 inhibitor restored bone volume, and reversed or normalized marrow adiposity. Ex vivo studies showed that PTH and GSK-3 inhibitor increased the ratio of colony forming marrow stromal progenitors (CFU-fs) that were alkaline phosphatase positive (putative osteoblasts). Our results suggest that the bone anabolic actions of PTH and GSK-3 inhibitor in vivo involve concerted effects on mesenchymal lineages; osteoblasts, chondrocytes, and adipocytes.

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.21374DOI Listing

Publication Analysis

Top Keywords

gsk-3 inhibitor
8
changes osteoblast
4
osteoblast chondrocyte
4
chondrocyte adipocyte
4
adipocyte lineages
4
lineages mediate
4
mediate bone
4
bone anabolic
4
anabolic actions
4
pth
4

Similar Publications

The aim was to explore the efficiency of Tideglusib in bone tissue healing by carrying it with different scaffolds on rat calvarial lesions. Twentyfour male Dawley rats were utilized. Two bone defects of 5 mm in diameter were formed (n = 8).

View Article and Find Full Text PDF

Glycogen synthase kinase-3 (GSK-3) plays a key role in several biochemical pathways and is an attractive target for pharmacological intervention. We prepared a series of analogs of a highly selective thiazolidinethione inhibitor of GSK-3. The structure-activity relationship indicated a precise structural requirement for potent inhibition.

View Article and Find Full Text PDF

Background: Approximately 30% of the non-small cell lung cancer (NSCLC) patients which harbor no recognizable oncogenic driver mutation are not eligible for targeted therapy. Functional drug screening of tumor cells helps to identify susceptible drug targets not recognized by gene panels for targeted mutation analysis. The aim of this study is to characterize the BH1406 cell line carrying an activating SOS1 mutation and to check its sensitivity to cognate inhibitors.

View Article and Find Full Text PDF

Discovery of Dual Targeting GSK-3β/HIV-1 Reverse Transcriptase Inhibitors as Neuroprotective Antiviral Agents.

ACS Chem Neurosci

January 2025

Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, United States.

Glycogen synthase kinase-3 beta (GSK-3β or GSK-3B) is a serine-threonine kinase involved in various pathways and cellular processes. Alteration in GSK-3β activity is associated with several neurological diseases including Alzheimer's disease (AD), bipolar disorder, and rare diseases like Rett syndrome. GSK-3β is also implicated in HIV-associated dementia (HAD), as it is upregulated in HIV-1-infected cells and plays a role in neuronal dysfunction.

View Article and Find Full Text PDF

Alkannin Induces G2/M-Phase Arrest, Apoptosis, and Inhibition of Invasion by Targeting GSK3β in Esophageal Squamous Cell Carcinoma.

Drug Des Devel Ther

December 2024

Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi, 832003, People's Republic of China.

Purpose: Esophageal squamous cell carcinoma (ESCC) is the most common malignant tumor of the upper gastrointestinal tract, characterized by high mortality and poor prognosis. There is an urgent need for the development of more effective drugs. Alkannin has been shown to inhibit the progression of various cancers, but its inhibitory effects on ESCC remain unclear.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!