1α,25(OH)2D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60 activated matrix vesicle metalloproteinases

Growth plate chondrocytes produce proteoglycan-rich type II collagen extracellular matrix (ECM). During cell maturation and hypertrophy, ECM is reorganized via a process regulated by 1 alpha,25(OH)(2)D-3 and involving matrix metalloprotemases (MMPs), including MMP-3 and MMP2. 1 alpha,25(OH)(2)D-3 regulates MMP incorporation into matrix vesicles (MVs), where they are stored until released. Like plasma membranes (PM). MVs contain the 1 alpha.25(OH)(2)D-3-binding protein ERp60, phospholipase A(2) (PLA(2)), and caveolin-1, but appear to lack nuclear Vitamin D receptors (VDRs). Chondrocytes produce 1 alpha,25(OH)(2)D-3 (10(-8) M), which binds ERp60, activating PLA(2), and resulting lysophospholipids lead to MV membrane disorganization, releasing active MMPs. MV MMP-3 activates TGF-beta 1 stored in the ECM as large latent TGF-beta 1 complexes. consisting of latent TGF-beta 1 binding protein, latency associated peptide, and latent TGF-beta 1. Others have shown that MMP2 specifically activates TGF-beta 2. TGF-beta 1 regulates 1 alpha,25(OH)(2)D-3-production, providing a mechanism for local control of growth factor activation. 1 alpha,25(OH)(2)D-3 activates PKCu in the PM via ERp60-signaling through PLA2, lysophospholipid production, and PLC beta. It also regulates distribution of phospholipids and PKC isoforms between MVs and PMs, enriching the MVs in PKCC. Direct activation of MMP-3 in MVs requires ERp60. However, when MVs are treated with 1 alpha,25(OH)(2)D-3, PKCC activity is decreased and PKCa is unaffected, suggesting a more complex feedback mechanism, potentially involving MV lipid signaling. (c) 2006 Elsevier Ltd. All rights reserved.