The vitamin D receptor (VDR), its requisite hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), as well as a host of nuclear receptor coactivators and corepressors coordinately control the expression of select genes and gene networks to impact bone by increasing intestinal calcium absorption and by directly affecting osteoblast proliferation, differentiation, and function. Meningioma-1 (MN1) is one such target gene that VDR and 1,25(OH)2D3 regulate in osteoblasts. MN1 is a coactivator of VDR and other nuclear receptors and it is needed for full ligand-induced activity of the VDR. The significance of MN1 in skeletal biology is suggested by the phenotype of the MN1 null mouse model which displays cranial skeletal anomalies in intramembranous ossification. In vitro data support an important role for this novel factor in the osteoblast and in skeletal biology. For example, MN1 is expressed in numerous osteoblastic cell lines including primary osteoblasts, its expression is increased during osteoblast differentiation, MN1 ablation dramatically impacts osteoblast morphology, osteoblast proliferation, osteoblast differentiation, 1,25(OH)2D3-activated gene expression, and 1,25(OH)2D3-stimulated osteoclastogenesis in co-culture studies. However, these in vitro approaches do not address the physiological relevance of MN1 in the postnatal skeleton. Due to postnatal lethality of the global MN1KO model, this critical poin of MN1 biology in the skeleton has remained unaddressed. In this current proposal, we present preliminary data on the development of a new mouse model that addresses this issue. Our laboratory developed a mouse with osteoblast-targeted ablation of the murine MN1 gene using the Col?1(I)-cre deletor strain combined with a conditional allele in which exon 1 of the murine MN1 gene is flanked by loxP sites. The Col?1(I)-cre+MN1fl/fl mice displayed a gender-selective and compartment-selective undermineralized skeletal phenotype at 20 weeks of age. These defects are reminiscent of those observed in early bone loss in young adults during the normal aging process in human and rodent models. These new data implicate MN1 in more global skeletal remodeling independent of VDR and the vitamin D endocrine system. This newest model has the potential to uncover new insight into potential mechanisms and biologies involved in early trabecular bone loss in young, adult mammals. Thus, the overall single research goal of this proposal is to characterize the detailed skeletal phenotype of this new model and establish the significance of MN1 in postnatal skeletal physiology.

Public Health Relevance

The mammalian skeleton is a dynamic system that is continuously remodeling throughout one's lifetime in order to maintain appropriate mineral homeostasis and adaptation to stress. Skeletal remodeling requires a balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Any disruption in the opposing activities of these cells results in a variety of metabolic bone diseases, the most common of which is osteoporosis. Osteoporosis is characterized by a progressive destruction of skeletal microarchitecture resulting in bone density loss and increased fracture risk. Despite advances in the prevention and treatment of osteoporosis, this disorder affects over 10 million Americans and causes substantial mortality and morbidity. Thus, understanding the complexities of skeletal homeostasis is essential for developing novel preventative and therapeutic strategies to combat osteoporosis. This proposal focuses on a newly identified transcriptional coactivator termed Meningioma-1 (MN1), that we have characterized as a key factor in controlling osteoblast proliferation, differentiation and function. The overall research goal is to prove that MN1 is an essential factor involved in maintaining global skeletal integrity n mammals using a newly developed mouse model in which MN1 has been selectively ablated from mature osteoblasts and osteocytes.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Chen, Faye H
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Case Western Reserve University
Schools of Medicine
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