PTH and Vitamin D Repress DMP1 in Cementoblasts.
A complex feedback mechanism between parathyroid hormone (PTH), 1,25(OH)2D3 (1,25D), and fibroblast growth factor 23 (FGF-23) maintains mineral homeostasis, in part by regulating calcium and phosphate absorption/reabsorption. Previously, we showed that 1,25D regulates mineral homeostasis by repressing dentin matrix protein 1 (DMP1) via the vitamin D receptor pathway. Similar to 1,25D, PTH may modulate DMP1, but the underlying mechanism remains unknown. Immortalized murine cementoblasts (OCCM.30), similar to osteoblasts and known to express DMP1, were treated with PTH (1-34). Real-time quantitative polymerase chain reaction (PCR) and Western blot revealed that PTH decreased DMP1 gene transcription (85%) and protein expression (30%), respectively. PTH mediated the downregulation of DMP1 via the cAMP/protein kinase A (PKA) pathway. Immunohistochemistry confirmed the decreased localization of DMP1 in vivo in cellular cementum and alveolar bone of mice treated with a single dose (50 µg/kg) of PTH (1-34). RNA-seq was employed to further identify patterns of gene expression shared by PTH and 1,25D in regulating DMP1, as well as other factors involved in mineral homeostasis. PTH and 1,25D mutually upregulated 36 genes and mutually downregulated 27 genes by ≥2-fold expression (P ≤ 0.05). Many identified genes were linked with the regulation of bone/tooth homeostasis, cell growth and differentiation, calcium signaling, and DMP1 transcription. Validation of RNA-seq results via PCR array confirmed a similar gene expression pattern in response to PTH and 1,25D treatment. Collectively, these results suggest that PTH and 1,25D share complementary effects in maintaining mineral homeostasis by mutual regulation of genes/proteins associated with calcium and phosphate metabolism while also exerting distinct roles on factors modulating mineral metabolism. Furthermore, PTH may modulate phosphate homeostasis by downregulating DMP1 expression via the cAMP/PKA pathway. Targeting genes/proteins mutually governed by PTH and 1,25D may be a viable approach for designing new therapies for preserving mineralized tissue health.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA le.wang@nih.gov.
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Wang
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
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Tran
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA Department of Prosthodontics and Periodontics, Division of Periodontics, School of Dentistry, Campinas State University, Piracicaba, SP, Brazil.
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Nociti
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
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Thumbigere-Math
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
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BL
Foster
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA.
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Krieger
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA Department of Prosthodontics and Periodontics, Division of Periodontics, School of Dentistry, Campinas State University, Piracicaba, SP, Brazil.
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Kantovitz
School of Dentistry, University of Michigan, Ann Arbor, MI, USA Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
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Novince
School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
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Koh
School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
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McCauley
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
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Somerman
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D003739:Dental Cementum / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D000089703:Fibroblast Growth Factor-23; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D010281:Parathyroid Hormone / Q000494:pharmacology* / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D014807:Vitamin D / Q000494:pharmacology* / Q000502:physiology
C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D014807:Vitamin D; D000089703:Fibroblast Growth Factor-23; D017868:Cyclic AMP-Dependent Protein Kinases
1,25D; RNA sequencing; dentin matrix protein 1; hormonal regulation; mineral homeostasis; parathyroid hormone