Abstract
The present review aims to systematically and critically analyze the current knowledge on phospholipases and their role in physiological and pathological mineralization undertaken by mineralization competent cells. Cellular lipid metabolism plays an important role in biological mineralization. The physiological mechanisms of mineralization are likely to take place in tissues other than in bones and teeth under specific pathological conditions. For instance, vascular calcification in arteries of patients with renal failure, diabetes mellitus or atherosclerosis recapitulates the mechanisms of bone formation. Osteoporosis—a bone resorbing disease—and rheumatoid arthritis originating from the inflammation in the synovium are also affected by cellular lipid metabolism. The focus is on the lipid metabolism due to the effects of dietary lipids on bone health. These and other phenomena indicate that phospholipases may participate in bone remodelling as evidenced by their expression in smooth muscle cells, in bone forming osteoblasts, chondrocytes and in bone resorbing osteoclasts. Among various enzymes involved, phospholipases A1 or A2, phospholipase C, phospholipase D, autotaxin and sphingomyelinase are engaged in membrane lipid remodelling during early stages of mineralization and cell maturation in mineralization-competent cells. Numerous experimental evidences suggested that phospholipases exert their action at various stages of mineralization by affecting intracellular signaling and cell differentiation. The lipid metabolites—such as arachidonic acid, lysophospholipids, and sphingosine-1-phosphate are involved in cell signaling and inflammation reactions. Phospholipases are also important members of the cellular machinery engaged in matrix vesicle (MV) biogenesis and exocytosis. They may favour mineral formation inside MVs, may catalyse MV membrane breakdown necessary for the release of mineral deposits into extracellular matrix (ECM), or participate in hydrolysis of ECM. The biological functions of phospholipases are discussed from the perspective of animal and cellular knockout models, as well as disease implications, development of potent inhibitors and therapeutic interventions.
Highlights
Bone Biology and Physiological MineralizationThe extracellular matrix (ECM) mineralization is a physiological process occurring in bone and teeth during skeletal growth in growth plate cartilage
Experimental evidence of the presence of specific types of PLA2s such as secreted PLA2 (sPLA2)-IIA, sPLA2-V and sPLA2-X, cPLA-IVA and iPLA2β in chondrocytes arise from analysis of human synovial fluid, especially from rheumatoid arthritis (RA) or OA patients or from the effects of cell stimulation with interleukin-1 (IL-1) and tumor necrosis factor (TNF). sPLA2-IIA was found in human synovial fluid of arthritic knee [123,124]
The cells interact with surfaces through integrins, which signal by the same pathways used by 1α,25(OH)2D3, i.e., they activate protein kinase C (PKC) via Phospholipase C (PLC) and protein kinase A via PLA2
Summary
The extracellular matrix (ECM) mineralization is a physiological process occurring in bone and teeth during skeletal growth in growth plate cartilage In these tissues, this process is maintained by mineralization-competent cells, e.g., osteoblasts, odontoblasts, and hypertrophic chondrocytes. Hypertrophic chondrocytes direct the mineralization of the surrounding matrix, attract blood vessels and attract chondroclasts (closely related or identical to osteoclasts) [7] These cells direct adjacent perichondrial cells to become osteoblasts. Mineralization-competent cells differentiate under the control of the runt-related transcription factor 2 (Runx2) They are able to secrete ECM, principally composed of fibrillar collagen, in which the calcium phosphate crystals with the hydroxyapatite (HA) structure are deposited [10]. The initiation of formation of calcium phosphate deposits is likely to start at matrix vesicles (MVs) [11], which are released by the mineralization-competent cells into ECM. FGF23 null mice have soft tissue calcifications, severe growth retardation, abnormalities of bone mineralization, a markedly shortened lifespan, and abnormalities of glucose metabolism [19,20]
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