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

Abstract

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 1α,25 (OH) 2 D 3 and involving matrix metalloproteinases (MMPs), including MMP-3and MMP-2. 1α,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 1α,25(OH) 2 D 3 -binding protein ERp60, phospholipase A 2 (PLA 2 ), and caveolin-1, but lack nuclear vitamin D receptors (VDRs). Chondrocytes produce 1α,25(OH) 2 D 3 (10 −8 M), which binds ERp60, activating PLA 2 , and resulting lysophospholipids lead MV membrane disorganization, releasing active MMPs. MV MMP-3 activates TGF-β1 stored in the ECM as large latent TGF-β1 complexes, consisting of latent TGF-β1 binding protein, latency associated peptide, and latent TGF-β1. Others have shown that MMP-2 specifically activates TGF-β2. TGF-β1 regulates 1α,25(OH) 2 D 3 -production, providing a mechanism for local control of growth factor activation. 1α,25(OH) 2 D 3 activates PKCα in the PM via ERp60-signaling through PLA 2 , lysophospholipid production, and PLCβ. It also regulates distribution of phospholipids and PKC isoforms between MVs and PMs, enriching the MVs in PKCζ. Direct activation of MMP-3 in MVs requires ERp60. However, when MVs are treated with 1α,25 (OH) 2 D 3 , PKCζ activity is decreased and PKCα is unaffected, suggesting a more complex feedback mechanism, potentially involving MV lipid signaling.

Terminal Differentiation of Chick Embryo Chondrocytes Requires Shedding of a Cell Surface Protein That Binds 1,25-Dihydroxyvitamin D3

“…1,25 D3 MARRS receptor-positive membrane vesicle-like structures were localized to the extracellular matrix of MO6-G3 cells, but a proteolytic cleavage and/or the production of a soluble form of 1,25 D3 MARRS receptor was also taken into account (39). Both states, the association of full-length 1,25 D3 MARRS receptor to matrix vesicles budding into the extracellular matrix (40) and the occurrence of shed fragments far off the cells, however, lead to a decline of protein content on the chondrocyte surface, where the vitamin D signaling is mediated.…”

ERp57/GRP58: A protein with multiple functions

“…These data suggest that ERp57 is an important initiator of 1,25(OH) 2 D 3 -stimulated membrane signaling pathways, which have both genomic and non-genomic effects during osteoblast maturation [45]. Boyan et al have also shown that the process of extracellular matrix reorganization brought up by chondrocytes is regulated by 1,25(OH) 2 D 3 interacting with ERp57, contained in the matrix vesicles [44]. In NB4 leukemia cells, ERp57 has been found to interact with NFκB, possibly at the level of the cell membrane, but certainly in the cytoplasm, and this complex is induced to translocate to the nucleus by the action of 1,25(OH) 2 D 3 and phorbol ester [49].…”

“…Rapid responses are not expected to be the result of the involvement of the classical vitamin D receptor (VDR), which operates through binding to DNA and the activation of gene expression, and therefore requires longer times to produce detectable events. The rapid cell response (seconds or minutes) after stimulation with 1α,25-(OH) 2 D 3 activates numerous cascades of signal transduction, involving signaling proteins such as phospholipases C (PLC) and A 2 (PLA 2 ), protein kinases C (PKC) and ERK (extracellular response activated kinase), all of which have been shown to respond to the formation of the ERp57-1α,25-(OH) 2 D 3 complex [44,45]. PKCα and PKCβ are both activated by 1α,25-(OH) 2 D 3 binding to ERp57 in isolated intestinal epithelial cells from chicks, with subsequent stimulation of phosphate uptake [43,46].…”

Vitamin D with asthma and COPD: not a false hope? A systematic review and meta-analysis

“…The second is lung tissue remodeling. Indirectly or directly, vitamin D regulates extracellular matrix homeostasis in tissues other than bone, within particular lung and skin tissue via the control of transforming growth factor-b, matrix metalloproteinase and plasminogen activator systems (Boyan et al, 2007). Immune modulation and peripheral muscle function should also be considered.…”