PMID- 38505222 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240321 IS - 2473-4039 (Electronic) IS - 2473-4039 (Linking) VI - 8 IP - 3 DP - 2024 Feb TI - Pten knockout in mouse preosteoblasts leads to changes in bone turnover and strength. PG - ziad016 LID - 10.1093/jbmrpl/ziad016 [doi] LID - ziad016 AB - Bone development and remodeling are controlled by the phosphoinositide-3-kinase (Pi3k) signaling pathway. We investigated the effects of downregulation of phosphatase and tensin homolog (Pten), a negative regulator of Pi3k signaling, in a mouse model of Pten deficiency in preosteoblasts. We aimed to identify mechanisms that are involved in the regulation of bone turnover and are linked to bone disorders. Femora, tibiae, and bone marrow stromal cells (BMSCs) isolated from mice with a conditional deletion of Pten (Pten cKO) in Osterix/Sp7-expressing osteoprogenitor cells were compared to Cre-negative controls. Bone phenotyping was performed by muCT measurements, bone histomorphometry, quantification of bone turnover markers CTX and procollagen type 1 N propeptide (P1NP), and three-point bending test. Proliferation of BMSCs was measured by counting nuclei and Ki-67-stained cells. In vitro, osteogenic differentiation capacity was determined by ALP staining, as well as by detecting gene expression of osteogenic markers. BMSCs from Pten cKO mice were functionally different from control BMSCs. Osteogenic markers were increased in BMSCs derived from Pten cKO mice, while Pten protein expression was lower and Akt phosphorylation was increased. We detected a higher trabecular bone volume and an altered cortical bone morphology in Pten cKO bones with a progressive decrease in bone and tissue mineral density. Pten cKO bones displayed fewer osteoclasts and more osteoblasts (P = .00095) per trabecular bone surface and a higher trabecular bone formation rate. Biomechanical analysis revealed a significantly higher bone strength (P = .00012 for males) and elasticity of Pten cKO femora. On the cellular level, both proliferation and osteogenic differentiation capacity of Pten cKO BMSCs were significantly increased compared to controls. Our findings suggest that Pten knockout in osteoprogenitor cells increases bone stability and elasticity by increasing trabecular bone mass and leads to increased proliferation and osteogenic differentiation of BMSCs. CI - (c) The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. FAU - Lorenz, Judith AU - Lorenz J AUID- ORCID: 0000-0002-5354-287X AD - Pediatric Research Center, Leipzig University, University Hospital for Children and Adolescents, Department for Child and Adolescent Medicine, 04103 Leipzig, Germany. FAU - Richter, Sandy AU - Richter S AD - Pediatric Research Center, Leipzig University, University Hospital for Children and Adolescents, Department for Child and Adolescent Medicine, 04103 Leipzig, Germany. FAU - Kirstein, Anna S AU - Kirstein AS AD - Pediatric Research Center, Leipzig University, University Hospital for Children and Adolescents, Department for Child and Adolescent Medicine, 04103 Leipzig, Germany. AD - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark. FAU - Kolbig, Florentien AU - Kolbig F AD - Pediatric Research Center, Leipzig University, University Hospital for Children and Adolescents, Department for Child and Adolescent Medicine, 04103 Leipzig, Germany. FAU - Nebe, Michele AU - Nebe M AD - Pediatric Research Center, Leipzig University, University Hospital for Children and Adolescents, Department for Child and Adolescent Medicine, 04103 Leipzig, Germany. FAU - Schulze, Marco AU - Schulze M AD - Saxon Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany. FAU - Kiess, Wieland AU - Kiess W AD - Pediatric Research Center, Leipzig University, University Hospital for Children and Adolescents, Department for Child and Adolescent Medicine, 04103 Leipzig, Germany. FAU - Spitzbarth, Ingo AU - Spitzbarth I AD - Faculty of Veterinary Medicine, Institute of Veterinary Pathology, Leipzig University, 04103 Leipzig, Germany. FAU - Kloting, Nora AU - Kloting N AD - Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum Munchen, Leipzig University and University Hospital Leipzig, 04103 Leipzig, Germany. FAU - Le Duc, Diana AU - Le Duc D AD - Institute of Human Genetics, Leipzig University, 04103 Leipzig, Germany. FAU - Baschant, Ulrike AU - Baschant U AD - Department of Medicine III, Technische Universitat Dresden, 01309 Dresden, Germany. FAU - Garten, Antje AU - Garten A AD - Pediatric Research Center, Leipzig University, University Hospital for Children and Adolescents, Department for Child and Adolescent Medicine, 04103 Leipzig, Germany. LA - eng PT - Journal Article DEP - 20240104 PL - England TA - JBMR Plus JT - JBMR plus JID - 101707013 PMC - PMC10945711 OTO - NOTNLM OT - Pten OT - bone marrow OT - osteoprogenitor OT - osterix OT - stem cells COIS- None declared. EDAT- 2024/03/20 06:45 MHDA- 2024/03/20 06:46 PMCR- 2024/01/04 CRDT- 2024/03/20 04:05 PHST- 2023/05/24 00:00 [received] PHST- 2023/11/30 00:00 [revised] PHST- 2023/12/07 00:00 [accepted] PHST- 2024/03/20 06:46 [medline] PHST- 2024/03/20 06:45 [pubmed] PHST- 2024/03/20 04:05 [entrez] PHST- 2024/01/04 00:00 [pmc-release] AID - ziad016 [pii] AID - 10.1093/jbmrpl/ziad016 [doi] PST - epublish SO - JBMR Plus. 2024 Jan 4;8(3):ziad016. doi: 10.1093/jbmrpl/ziad016. eCollection 2024 Feb.