title: Maturation of cortical bone suppresses periosteal osteoprogenitor proliferation in a paracrine manner.
abstract: Periosteum contains enriched pools of osteogenic progenitors and is highly proliferative, thus giving this tissue a pivotal role in maintaining the diameter of the diaphyseal cortex and in recovery from fractures. Although periosteal proliferation has not been detected in normal bone, intense periosteal proliferation has been observed in pathologic states such as fracture, inflammation, and bone tumors. However, the mechanism by which periosteal osteoprogenitor proliferation is regulated remains poorly understood. To investigate this regulation mechanism, osteoblast/osteocyte-specific conditional knockout mice were developed lacking Smad4 and Osx, two factors that are essential for osteoblast differentiation and matrix mineralization. In Smad4 (Col) and Osx (Col) mice, osteocalcin, Dmp-1, and sclerostin expression were significantly decreased in the cortical bone. Interestingly, although Cre activity was not observed in the periosteum, the proliferation of periosteal osteoprogenitors was enhanced in Smad4 (Col) and Osx (Col) mice, as assessed by 5'-bromo-2'deoxyuridine incorporation and proliferating cell nuclear antigen localization. Since Wnt signaling is a major factor affecting periosteal proliferation, we evaluated Wnt signaling in the periosteum. The expression levels of β-catenin and Lef-1 were increased in the periosteal osteoprogenitors. Moreover, the mRNA levels of β-catenin, cyclin D1, Lef-1, and Axin2, all of which are Wnt target genes, were significantly increased in the periosteum of both Smad4 (Col) and Osx (Col) mice. These results indicated that extracellular proteins secreted by mature osteoblasts and osteocytes suppress the proliferation of periosteal osteoprogenitors by blocking Wnt signaling in a paracrine manner. Our data suggest a new concept of periosteal bone healing and periosteal bone formation.
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, 567 Baekje-Daero Deokjin-Gu, Jeonju, Jeonbuk, 54896, Republic of Korea.|Cluster for Craniofacial Development and Regeneration Research and Institute of Oral Biosciences, Chonbuk National University School of Dentistry, 567 Baekje-Daero Deokjin-Gu, Jeonju, Jeonbuk, 54896, Republic of Korea.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Moon
authors.affiliation: Cluster for Craniofacial Development and Regeneration Research and Institute of Oral Biosciences, Chonbuk National University School of Dentistry, 567 Baekje-Daero Deokjin-Gu, Jeonju, Jeonbuk, 54896, Republic of Korea.
authors.forename: Chi-Young
authors.initials: CY
authors.lastname: Yun
authors.affiliation: Cluster for Craniofacial Development and Regeneration Research and Institute of Oral Biosciences, Chonbuk National University School of Dentistry, 567 Baekje-Daero Deokjin-Gu, Jeonju, Jeonbuk, 54896, Republic of Korea.
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Orthopaedic Surgery, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54896, Republic of Korea.
authors.forename: Jung Ryul
authors.initials: JR
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, 567 Baekje-Daero Deokjin-Gu, Jeonju, Jeonbuk, 54896, Republic of Korea. bhpark@jbnu.ac.kr.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
authors.affiliation: Cluster for Craniofacial Development and Regeneration Research and Institute of Oral Biosciences, Chonbuk National University School of Dentistry, 567 Baekje-Daero Deokjin-Gu, Jeonju, Jeonbuk, 54896, Republic of Korea. oasis@jbnu.ac.kr.
authors.forename: Eui-Sic
authors.initials: ES
authors.lastname: Cho
mesh_terms: D000818:Animals; D015415:Biomarkers; D002113:Calcification, Physiologic; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D000071538:Cortical Bone / Q000502:physiology*; D055785:Gene Knockdown Techniques; D018390:Gene Targeting; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism; D010011:Osteocytes / Q000378:metabolism; D010012:Osteogenesis; D019899:Paracrine Communication; D010521:Periosteum / Q000166:cytology*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051901:Smad4 Protein; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins
keywords: Extracellular matrix; Mineralization; Periosteum; Proliferation; WNT signaling