The metalloproteinase PAPP-A is required for IGF-dependent chondrocyte differentiation and organization.

Autor: Harboe M; Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, 8000, Aarhus C, Denmark., Kjaer-Sorensen K; Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, 8000, Aarhus C, Denmark., Füchtbauer EM; Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, 8000, Aarhus C, Denmark., Fenton RA; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Thomsen JS; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Brüel A; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Oxvig C; Department of Molecular Biology and Genetics, Aarhus University, Universitetsbyen 81, 8000, Aarhus C, Denmark. co@mbg.au.dk.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Aug 29; Vol. 14 (1), pp. 20161. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1038/s41598-024-71062-6
Abstrakt: Insulin-like growth factor (IGF) signaling is required for proper growth and skeletal development in vertebrates. Consequently, its dysregulation may lead to abnormalities of growth or skeletal structures. IGF is involved in the regulation of cell proliferation and differentiation of chondrocytes. However, the availability of bioactive IGF may be controlled by antagonizing IGF binding proteins (IGFBPs) in the circulation and tissues. As the metalloproteinase PAPP-A specifically cleaves members of the IGFBP family, we hypothesized that PAPP-A activity liberates bioactive IGF in cartilage. In PAPP-A knockout mice, the femur length was reduced and the mice showed a disorganized columnar organization of growth plate chondrocytes. Similarly, zebrafish lacking pappaa showed reduced length of Meckel's cartilage and disorganized chondrocytes, reminiscent of the mouse knockout phenotype. Expression of chondrocyte differentiation markers (sox9a, ihha, and col10a1) was markedly affected in Meckel's cartilage of pappaa knockout zebrafish, indicating that differentiation of chondrocytes was compromised. Additionally, the zebrafish pappaa knockout phenotype was mimicked by pharmacological inhibition of IGF signaling, and it could be rescued by treatment with exogenous recombinant IGF-I. In conclusion, our data suggests that IGF activity in the growing cartilage, and hence IGF signaling in chondrocytes, requires the presence of PAPP-A. The absence of PAPP-A causes aberrant chondrocyte organization and compromised growth in both mice and zebrafish.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: