Expression of Noggin and Gremlin1 and its implications in fine-tuning BMP activities in mouse cartilage tissues

Xiaodan Yu, Hiroko Kawakami, Naoyuki Tahara, Merissa Olmer, Shinichi Hayashi, Ryutaro Akiyama, Anindya Bagchi, Martin Lotz, Yasuhiko Kawakami

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5 Scopus citations

Abstract

Increasing evidence supports the idea that bone morphogenetic proteins (BMPs) regulate cartilage maintenance in the adult skeleton. The aim of this study is to obtain insight into the regulation of BMP activities in the adult skeletal system. We analyzed expression of Noggin and Gremlin1, BMP antagonists that are known to regulate embryonic skeletal development, in the adult skeletal system by Noggin-LacZ and Gremlin1-LacZ knockin reporter mouse lines. Both reporters are expressed in the adult skeleton in a largely overlapping manner with some distinct patterns. Both are detected in the articular cartilage, pubic symphysis, facet joint in the vertebrae, and intervertebral disk, suggesting that they regulate BMP activities in these tissues. In a surgically induced knee osteoarthritis model in mice, expression of Noggin mRNA was lost from the articular cartilage, which correlated with loss of BMP2/4 and pSMAD1/5/8, an indicator of active BMP signaling. Both reporters are also expressed in the sterna and rib cartilage, suggesting an extensive role of BMP antagonism in adult cartilage tissue. Moreover, Noggin-LacZ was detected in sutures in the skull and broadly in the nasal cartilage, while Gremlin1-LacZ exhibits a weaker and more restricted expression domain in the nasal cartilage. These results suggest broad regulation of BMP activities by Noggin and Gremlin1 in cartilage tissues in the adult skeleton, and that BMP signaling and its antagonism by NOGGIN play a role in osteoarthritis development.

Original languageEnglish (US)
Pages (from-to)1671-1682
Number of pages12
JournalJournal of Orthopaedic Research
Volume35
Issue number8
DOIs
StatePublished - Aug 2017

Bibliographical note

Funding Information:
We thank Drs. Laura Gammill, Yasushi Nakagawa, Michael O'Connor, and Jonathan Slack for the use of their equipment. We are grateful to Drs. Michael O'Connor and Aidan Peterson for help in pSMAD1/5/8 staining, to Midori Usuki-Filiz, Yumi Motokura, Holly Johnson, Kristina Weimer, Jenna Matson, Sho Kawakami, Malina Peterson, and Elizabeth West for excellent technical assistance, to the Medical Student Internship Program at the Okayama University School of Medicine, Japan. We also thank Dr. Richard Harland for Nog-LacZ and Grem1-LacZ knockin mouse lines, and Dr. Brian Harfe for the whole mount LacZ staining protocol. Research reported in this publication was supported by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases to YK (AR064195) and National Institute on Aging to ML (AG007996). Xiaodan Yu was partially supported by the Undergraduate Research Opportunity Program at the University of Minnesota.

Keywords

  • Gremlin1
  • Noggin
  • bone morphogenetic protein antagonist
  • cartilage tissue
  • osteoarthritis

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