Expression of the type 1 lysophosphatidic acid receptor in osteoblastic cell lineage controls both bone mineralization and osteocyte specification |
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| Institution: | 1. Institute of Behavioural Neuroscience, Department of Experimental Psychology, Division of Psychology and Language Sciences, University College London, London, UK;1. Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, A1B 3V6, Canada;2. Signal Transduction Research Group, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada;1. São Paulo State University (UNESP), School of Sciences, Bauru, SP, Brazil;2. São Paulo State University (UNESP), Medical School, Botucatu, SP, Brazil;3. Lauro de Souza Lima Institute, Bauru, SP, Brazil;4. University of Brasília (UnB), Institute of Biological Sciences Brasília, Federal District, Brazil;5. University of São Paulo (USP), Institute of Biomedical Sciences, SP, Brazil;6. Federal University of Mato Grosso do Sul (UFMS), Medical School, Campo Grande, MS, Brazil;1. Centre of Inflammation and Metabolism, Centre for Physical Activity Research (CIM /CFAS), Rigshospitalet, Copenhagen, Denmark;2. Department of Oncology, Rigshospitalet, Copenhagen, Denmark;3. Department of Gastro-Intestinal Surgery, Herlev Hospital, Denmark;4. Digestive Disease Center, Bispebjerg Hospital, Copenhagen, Denmark;5. Center for Surgical Science, Zealand University Hospital, Roskilde, Denmark;6. Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University, Herlev, Denmark |
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| Abstract: | Lysphosphatidic acid (LPA) is a major natural bioactive lipid mediator whose biological functions affect multiple organs. These include bone as demonstrated by global Lpar1-knockout mice (Lpar1−/−) which present a bone growth defect. LPA acts on all bone cells including osteoblasts, that are responsible for bone formation, and osteoclasts, which are specialized cells that resorb bone. LPA appears as a potential new coupling molecule during bone remodeling. LPA1 is the most ubiquitous LPA receptor among the six LPA receptor family members (LPA1–6). To better understand the specific role of LPA via its receptor LPA1 in osteoblastic cell lineage we generated osteoblast-specific Lpar1 knockout mice (Lpar1-∆Ob) by crossing Lpar1flox/flox and Osx:Cre+ mouse lines. Lpar1-∆Ob mice do not recapitulate the bone defects of Lpar1−/− mice but revealed reduced bone mineralization and decreased cortical thickness, as well as increased bone porosity associated with an augmentation in the lacunae areas of osteocyte and their apoptotic yield. In vitro, primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1−/− osteoblasts revealed a remarkable premature expression of alkaline phosphatase, reduced cell proliferation associated with decreased YAP-P nuclear accumulation, and reduced mineralization activity. Osteocyte specification is markedly impaired as demonstrated by reduced expression of early (E11) and late (DMP1, DKK1, SOST) osteocyte markers ex vivo in enriched osteocytic fractions of Lpar1-∆Ob mouse bone explants. In addition, E11 expression and dendrite formation induced by FGF2 are markedly impaired in both primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1−/− osteoblasts. Taken together these results suggest a new role for LPA in bone mass control via bone mineralization and osteocyte function. |
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