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First published online 3 December 2003
doi: 10.1242/dev.00901

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A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage

Naoki Nakayama^1,*,, Chun-ya E. Han¹, Linh Cam², Jae I. Lee¹, Jim Pretorius³, Seth Fisher⁴, Robert Rosenfeld⁴, Sheila Scully³, Ryuichi Nishinakamura⁵, Diane Duryea³, Gwyneth Van³, Brad Bolon³, Takashi Yokota⁵ and Ke Zhang²

¹ Department of Metabolic Disorders, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA
² Department of Cancer Biology, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA
³ Department of Pathology, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA
⁴ Department of Protein Science, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA
⁵ Department of Stem Cell Regulation, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

Author for correspondence (e-mail: naoki.nakayama{at}petermac.org)

Accepted 2 October 2003

We have identified a novel chordin-like protein, CHL2, which is structurally most homologous to CHL/neuralin/ventroptin. When injected into Xenopus embryos, CHL2 RNA induced a secondary axis. Recombinant CHL2 protein interacted directly with BMPs in a competitive manner to prevent binding to the type I BMP receptor ectodomain, and inhibited BMP-dependent induction of alkaline phosphatase in C2C12 cells. Thus, CHL2 behaves as a secreted BMP-binding inhibitor. In situ hybridization revealed that CHL2 expression is restricted to chondrocytes of various developing joint cartilage surfaces and connective tissues in reproductive organs. Adult mesenchymal progenitor cells expressed CHL2, and its levels decreased during chondrogenic differentiation. Addition of CHL2 protein to a chondrogenic culture system reduced cartilage matrix deposition. Consistently, CHL2 transcripts were weakly detected in normal adult joint cartilage. However, CHL2 expression was upregulated in middle zone chondrocytes in osteoarthritic joint cartilage (where hypertrophic markers are induced). CHL2 depressed chondrocyte mineralization when added during the hypertrophic differentiation of cultured hyaline cartilage particles. Thus, CHL2 may play negative roles in the (re)generation and maturation of articular chondrocytes in the hyaline cartilage of both developing and degenerated joints.

Key words: Secreted protein, Chordin, BMP, Inhibitor, Chondrocyte, Cartilage, Superficial zone, Joint, Osteoarthritis

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