Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton |
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| Affiliation: | 1. Department of Mechanical Engineering, University of Colorado Boulder, Boulder, CO, USA;2. Department of Orthopaedics, University of Colorado School of Medicine, Aurora, CO, USA;3. Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC, USA;4. Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA;5. Veterans Affairs, Eastern Colorado Health Care System, Denver, CO, USA;1. Department of Life Sciences, Theobald Science Center, Room 420, New York Institute of Technology, Old Westbury, NY 11568-8000, USA;2. Bioinformatics Core Facility, Stony Brook University, Stony Brook, NY 11794, USA;3. Department of Orthopaedics, HSC T18 Room 85, Stony Brook University, Stony Brook, NY 11794-8181, USA;1. Dept. of Clinical Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Norway;2. Dept. of Rheumatology, Laval University and CHU de Québec (CHUL) Research Centre, Quebec City, Canada;1. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States;2. Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States;1. Dept. of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794-5281, United States;2. Dept. of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, United States;3. UCB Pharma, Slough, UK |
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| Abstract: | Notch signaling is a key pathway controlling various cell fate decisions during embryogenesis and adult life. It is activated by binding of specific ligands to four different Notch receptors that are subsequently cleaved by presenilins to release an intracellular domain that enters the nucleus and activates specific transcription factors. While the skeletal analysis of various mouse models with activated or inactivated Notch signaling has demonstrated a general impact of this pathway on bone remodeling, the more recent identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome (HCS) has highlighted its human relevance. Since HCS is primarily characterized by skeletal defects, these latter findings led us to analyze the specific role of Notch2 in skeletal remodeling. After observing Notch2 expression in osteoblasts and osteoclasts, we utilized Runx2-Cre and Lyz2-Cre mice to inactivate Notch2 in cells of the osteoblast or osteoclast lineage, respectively. Whereas Notch2fl/fl/Lyz2-Cre mice did not display significant alterations of skeletal growth, bone mass or remodeling, Notch2fl/fl/Runx2-Cre mice progressively developed skeletal abnormalities in long bones. More specifically, these mice displayed a striking increase of trabecular bone mass in the proximal femur and the distal tibia at 6 and 12 months of age. Whereas undecalcified sectioning of the respective regions did not reveal impaired osteocyte differentiation as a potential trigger for the observed phenotype, ex vivo experiments with bone marrow cells identified an increased osteogenic capacity of Notch2fl/fl/Runx2-Cre cultures. Collectively, our findings demonstrate that Notch2 physiologically regulates bone remodeling by inhibiting trabecular bone formation in the appendicular skeleton. Understanding the underlying mechanisms may help to improve diagnosis and therapy of HCS. |
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