Cthrc1 is a positive regulator of osteoblastic bone formation.
Bone mass is maintained by continuous remodeling through repeated cycles of bone resorption by osteoclasts and bone formation by osteoblasts. This remodeling process is regulated by many systemic and local factors.We identified collagen triple helix repeat containing-1 (Cthrc1) as a downstream targe...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2008-09-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2527134?pdf=render |
| _version_ | 1828488758296576000 |
|---|---|
| author | Hiroaki Kimura Kin Ming Kwan Zhaoping Zhang Jian Min Deng Bryant G Darnay Richard R Behringer Takashi Nakamura Benoit de Crombrugghe Haruhiko Akiyama |
| author_facet | Hiroaki Kimura Kin Ming Kwan Zhaoping Zhang Jian Min Deng Bryant G Darnay Richard R Behringer Takashi Nakamura Benoit de Crombrugghe Haruhiko Akiyama |
| author_sort | Hiroaki Kimura |
| collection | DOAJ |
| description | Bone mass is maintained by continuous remodeling through repeated cycles of bone resorption by osteoclasts and bone formation by osteoblasts. This remodeling process is regulated by many systemic and local factors.We identified collagen triple helix repeat containing-1 (Cthrc1) as a downstream target of bone morphogenetic protein-2 (BMP2) in osteochondroprogenitor-like cells by PCR-based suppression subtractive hybridization followed by differential hybridization, and found that Cthrc1 was expressed in bone tissues in vivo. To investigate the role of Cthrc1 in bone, we generated Cthrc1-null mice and transgenic mice which overexpress Cthrc1 in osteoblasts (Cthrc1 transgenic mice). Microcomputed tomography (micro-CT) and bone histomorphometry analyses showed that Cthrc1-null mice displayed low bone mass as a result of decreased osteoblastic bone formation, whereas Cthrc1 transgenic mice displayed high bone mass by increase in osteoblastic bone formation. Osteoblast number was decreased in Cthrc1-null mice, and increased in Cthrc1 transgenic mice, respectively, while osteoclast number had no change in both mutant mice. In vitro, colony-forming unit (CFU) assays in bone marrow cells harvested from Cthrc1-null mice or Cthrc1 transgenic mice revealed that Cthrc1 stimulated differentiation and mineralization of osteoprogenitor cells. Expression levels of osteoblast specific genes, ALP, Col1a1, and Osteocalcin, in primary osteoblasts were decreased in Cthrc1-null mice and increased in Cthrc1 transgenic mice, respectively. Furthermore, BrdU incorporation assays showed that Cthrc1 accelerated osteoblast proliferation in vitro and in vivo. In addition, overexpression of Cthrc1 in the transgenic mice attenuated ovariectomy-induced bone loss.Our results indicate that Cthrc1 increases bone mass as a positive regulator of osteoblastic bone formation and offers an anabolic approach for the treatment of osteoporosis. |
| first_indexed | 2024-12-11T10:14:47Z |
| format | Article |
| id | doaj.art-9cf2c279f5ca4afaa8078c2aa3d54647 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T10:14:47Z |
| publishDate | 2008-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9cf2c279f5ca4afaa8078c2aa3d546472022-12-22T01:11:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-09-0139e317410.1371/journal.pone.0003174Cthrc1 is a positive regulator of osteoblastic bone formation.Hiroaki KimuraKin Ming KwanZhaoping ZhangJian Min DengBryant G DarnayRichard R BehringerTakashi NakamuraBenoit de CrombruggheHaruhiko AkiyamaBone mass is maintained by continuous remodeling through repeated cycles of bone resorption by osteoclasts and bone formation by osteoblasts. This remodeling process is regulated by many systemic and local factors.We identified collagen triple helix repeat containing-1 (Cthrc1) as a downstream target of bone morphogenetic protein-2 (BMP2) in osteochondroprogenitor-like cells by PCR-based suppression subtractive hybridization followed by differential hybridization, and found that Cthrc1 was expressed in bone tissues in vivo. To investigate the role of Cthrc1 in bone, we generated Cthrc1-null mice and transgenic mice which overexpress Cthrc1 in osteoblasts (Cthrc1 transgenic mice). Microcomputed tomography (micro-CT) and bone histomorphometry analyses showed that Cthrc1-null mice displayed low bone mass as a result of decreased osteoblastic bone formation, whereas Cthrc1 transgenic mice displayed high bone mass by increase in osteoblastic bone formation. Osteoblast number was decreased in Cthrc1-null mice, and increased in Cthrc1 transgenic mice, respectively, while osteoclast number had no change in both mutant mice. In vitro, colony-forming unit (CFU) assays in bone marrow cells harvested from Cthrc1-null mice or Cthrc1 transgenic mice revealed that Cthrc1 stimulated differentiation and mineralization of osteoprogenitor cells. Expression levels of osteoblast specific genes, ALP, Col1a1, and Osteocalcin, in primary osteoblasts were decreased in Cthrc1-null mice and increased in Cthrc1 transgenic mice, respectively. Furthermore, BrdU incorporation assays showed that Cthrc1 accelerated osteoblast proliferation in vitro and in vivo. In addition, overexpression of Cthrc1 in the transgenic mice attenuated ovariectomy-induced bone loss.Our results indicate that Cthrc1 increases bone mass as a positive regulator of osteoblastic bone formation and offers an anabolic approach for the treatment of osteoporosis.http://europepmc.org/articles/PMC2527134?pdf=render |
| spellingShingle | Hiroaki Kimura Kin Ming Kwan Zhaoping Zhang Jian Min Deng Bryant G Darnay Richard R Behringer Takashi Nakamura Benoit de Crombrugghe Haruhiko Akiyama Cthrc1 is a positive regulator of osteoblastic bone formation. PLoS ONE |
| title | Cthrc1 is a positive regulator of osteoblastic bone formation. |
| title_full | Cthrc1 is a positive regulator of osteoblastic bone formation. |
| title_fullStr | Cthrc1 is a positive regulator of osteoblastic bone formation. |
| title_full_unstemmed | Cthrc1 is a positive regulator of osteoblastic bone formation. |
| title_short | Cthrc1 is a positive regulator of osteoblastic bone formation. |
| title_sort | cthrc1 is a positive regulator of osteoblastic bone formation |
| url | http://europepmc.org/articles/PMC2527134?pdf=render |
| work_keys_str_mv | AT hiroakikimura cthrc1isapositiveregulatorofosteoblasticboneformation AT kinmingkwan cthrc1isapositiveregulatorofosteoblasticboneformation AT zhaopingzhang cthrc1isapositiveregulatorofosteoblasticboneformation AT jianmindeng cthrc1isapositiveregulatorofosteoblasticboneformation AT bryantgdarnay cthrc1isapositiveregulatorofosteoblasticboneformation AT richardrbehringer cthrc1isapositiveregulatorofosteoblasticboneformation AT takashinakamura cthrc1isapositiveregulatorofosteoblasticboneformation AT benoitdecrombrugghe cthrc1isapositiveregulatorofosteoblasticboneformation AT haruhikoakiyama cthrc1isapositiveregulatorofosteoblasticboneformation |