Sphingolipid metabolism and its role in the skeletal tissues

Abstract

The regulators affecting skeletal tissue formation and its maintenance include a wide array of molecules with very diverse functions. More recently, sphingolipids have been added to this growing list of regulatory molecules in the skeletal tissues. Sphingolipids are integral parts of various lipid membranes present in the cells and organelles. For a long time, these macromolecules were considered as inert structural elements. This view, however, has radically changed in recent years as sphingolipids are now recognized as important second messengers for signal-transduction pathways that affect cell growth, differentiation, stress responses and programmed death. In the current review, we discuss the available data showing the roles of various sphingolipids in three different skeletal cell types-chondrocytes in cartilage and osteoblasts and osteoclasts in bone. We provide an overview of the biology of sphingomyelin phosphodiesterase 3 (SMPD3), an important regulator of sphingolipid metabolism in the skeleton. SMPD3 is localized in the plasma membrane and has been shown to cleave sphingomyelin to generate ceramide, a bioactive lipid second messenger, and phosphocholine, an essential nutrient. SMPD3 deficiency in mice impairs the mineralization in both cartilage and bone extracellular matrices leading to severe skeletal deformities. A detailed understanding of SMPD3 function may provide a novel insight on the role of sphingolipids in the skeletal tissues.

Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

“…SMPD3 has been shown to regulate the mineralization of both these ECMs. In agreement with the strong Smpd3 expression reported in both chondrocytes and osteoblasts, SMPD3 deficiency affects the initiation of mineralization in both cartilage and bone (4,26). It was shown earlier that bone morphogenetic protein (BMP) signaling and chondro-osteogenic transcription factor RUNX2 might be involved in the regulation of Smpd3 expression (24,27).…”

“…In the developing long bones of mice, mineralized tissues first appear at about embryonic day 14, when the ECM synthesized by the late hypertrophic chondrocytes starts accumulating hydroxyapatite minerals (4,26). Concomitantly, osteoblast-derived ECM in the surrounding periosteum is also mineralized.…”

“…Recently, this enzyme has been identified to be a key regulator of skeletal development (2)(3)(4)(5)(6). SMPD3 cleaves sphingomyelin and generates ceramides, a class of lipid second messengers, and phosphocholine, an important intermediate for a number of metabolic pathways (7)(8)(9).…”

Osteocalcin Regulates Arterial Calcification Via Altered Wnt Signaling and Glucose Metabolism

“…Increased PiT‐1 expression leads to elevated intracellular phosphate and induces the osteogenic conversion of VSMCs . A parallel decrease in matrix Gla protein, an established inhibitor of arterial calcification was observed.…”

Novel eosinophilic gene expression networks associated with IgE in two distinct asthma populations

“…CCL23 is an eosinophilic chemokine, that has been identified as a possible biomarker for anti-IL13 targeted therapies (49, 50). Several of these are enzymes expressed within eosinophils, such as CLC, IDO1, SMPD3 , and SPNS3 , and the latter two are both involved in the sphingolipid pathways, known to mediate airway hyperresponsiveness and mast cell activation (51, 52). Another gene CAMK1 has been implicated as an asthma control gene(20), but has not been identified previously with IgE or an allergy-related phenotype among individuals diagnosed with asthma.…”