A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage.
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.
Nakayama
Naoki
N
Department of Metabolic Disorders, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. naoki.nakayama@petermac.org
Han
Chun-ya E
CY
Cam
Linh
L
Lee
Jae I
JI
Pretorius
Jim
J
Fisher
Seth
S
Rosenfeld
Robert
R
Scully
Sheila
S
Nishinakamura
Ryuichi
R
Duryea
Diane
D
Van
Gwyneth
G
Bolon
Brad
B
Yokota
Takashi
T
Zhang
Ke
K
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002356:Cartilage / Q000196:embryology*; D019902:Chondrocytes / Q000502:physiology*; D017124:Conserved Sequence; D017931:DNA Primers; D004625:Embryo, Nonmammalian / Q000502:physiology; D016326:Extracellular Matrix Proteins; D005260:Female; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010003:Osteoarthritis / Q000235:genetics*; D010920:Placenta / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014981:Xenopus / Q000196:embryology*
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; C481985:Chrdl2 protein, mouse; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D000469:Alkaline Phosphatase