Premium
1α,25‐Dihydroxyvitamin D 3 Promotes Vascularization of the Chondro‐osseous Junction by Stimulating Expression of Vascular Endothelial Growth Factor and Matrix Metalloproteinase 9
Author(s) -
Lin Roberto,
Amizuka Norio,
Sasaki Tomoyo,
Aarts Michelle M.,
Ozawa Hideharo,
Goltzman David,
Henderson Janet E.,
White John H.
Publication year - 2002
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2002.17.9.1604
Subject(s) - endochondral ossification , vascular endothelial growth factor , endocrinology , medicine , angiogenesis , chondrogenesis , cartilage , microbiology and biotechnology , biology , growth factor , vascular endothelial growth factor a , matrix metalloproteinase , chemistry , anatomy , receptor , vegf receptors
Vitamin D deficiency results in defects in endochondral bone development characteristic of rickets, which include elongation of the cartilaginous growth plates and disorganization of the primary spongiosa. These defects are caused in part by impaired cartilage mineralization and vascularization of the chondro‐osseous junction. Blood vessel invasion of mineralized cartilage is an essential step in endochondral ossification, providing access for cells that degrade cartilage as well as those that form bone. Vascular endothelial growth factor (VEGF) was shown to be a key regulator of this process when infusion of a dominant negative VEGF receptor effectively blocked vascular invasion and endochondral ossification in the growth plates of juvenile mice. Here, we show that the active metabolite of vitamin D 1α,25‐dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] directly stimulates transcription of mRNAs encoding VEGF121 and −165 isoforms in the CFK2 chondrogenic cell line. Enhanced VEGF expression also was evident in growth plate chondrocytes and osteoblasts in the tibia of juvenile mice treated systemically with 1α,25(OH) 2 D 3 . This was seen in conjunction with enhanced expression of matrix metalloproteinase (MMP) 9, which activates VEGF stored in the cartilage matrix, in osteoclastic cells adjacent to the chondro‐osseous junction. The alterations in VEGF and MMP‐9 expression were accompanied by enhanced vascular invasion of mineralized cartilage, as assessed by CD31 immunoreactivity. These results provide evidence that 1α,25(OH) 2 D 3 signaling stimulates VEGF and MMP‐9 gene expression and promotes neovascularization of the epiphyseal growth plate in vivo through increased availability of active growth factor.