Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection

Abstract

The human skeleton is a metabolically active system that is constantly regenerating via the tightly regulated and highly coordinated processes of bone resorption and formation. Emerging evidence reveals fascinating new insights into the role of sphingolipids, including sphingomyelin, sphingosine, ceramide, and sphingosine-1-phosphate, in bone homeostasis. Sphingolipids are a major class of highly bioactive lipids able to activate distinct protein targets including, lipases, phosphatases, and kinases, thereby conferring distinct cellular functions beyond energy metabolism. Lipids are known to contribute to the progression of chronic inflammation, and notably, an increase in bone marrow adiposity parallel to elevated bone loss is observed in most pathological bone conditions, including aging, rheumatoid arthritis, osteoarthritis, and osteomyelitis. Of the numerous classes of lipids that form, sphingolipids are considered among the most deleterious. This review highlights the important primary role of sphingolipids in bone homeostasis and how dysregulation of these bioactive metabolites appears central to many chronic bone-related diseases. Further, their contribution to the invasion, virulence, and colonization of both viral and bacterial host cell infections is also discussed. Many unmet clinical needs remain, and data to date suggest the future use of sphingolipid-targeted therapy to regulate bone dysfunction due to a variety of diseases or infection are highly promising. However, deciphering the biochemical and molecular mechanisms of this diverse and extremely complex sphingolipidome, both in terms of bone health and disease, is considered the next frontier in the field.

Keywords: bone; disease; infection; osteoporosis; sphingolipids.

Figure 1

Ceramide, the hub of the sphingolipid pathway, can be generated via different pathways. De novo synthesis, i.e., the single entry point into the cycle, begins in the ER with condensation of typically serine and palmitoyl-CoA to form 3-ketosphingosine. The 3-ketodihydrosphingosine is subsequently and rapidly converted to dihydroxyceramide prior to acylation to dihydroceramides by the action of dihydroceramide synthase. Dihydroceramide is then dehydrated by dihydrodesaturase (DES) to form ceramide, which is translocated to the Golgi complex. Ceramides can also be generated via the sphingomyelinase (SMase) pathway that degrades sphingomyelin or via the catabolic pathway that generates ceramides from sphingosine by ceramide synthase from glucosylceramides by acid β-glucosylceramidase or by C1P via the action of C1P phosphatase. Similarly, and in parallel, the reactions are reversible, and ceramides generate sphingomyelin through the activity of sphingomyelin synthase, sphingosine through the enzyme ceramidase within the lysosome, and C1P via ceramide kinase activity. Further, sphingosine can instead be converted to S1P via sphingosine kinase or instead irreversibly cleaved by ER-localized S1P lyase, leading to complete sphingolipid degradation, the single exit route within the sphingolipid pathway. The various enzymes involved within the pathway are highlighted in color.

Figure 2

A schematic showing the relationship between RANK, RANKL, and OPG in activating or inhibiting osteoclastic activity and subsequent bone resorption. The binding of RANKL to the membrane-bound receptor RANK results in the activation of osteoclastic activity. However, OPG acts as a decoy and, if present, will bind to RANKL, thereby preventing RANK–RANKL interaction and osteoclastic activation. Thus, bone formation versus resorption is fundamentally dependent on the RANKL:OPG ratio, where increased RANKL expression results in bone resorption and increased OPG in bone formation. Many cells secrete either or both OPG or RANKL or both (e.g., osteocytes, osteoblasts, BMSCs, B-lymphocytes, and megakaryocytes). Regulation of the cellular response occurs via mechanical, hormonal, and growth factor-induced signaling, among others, making the overall governance of this system highly complex.

Figure 3

A heat map showing how biomolecules, the gut microbiome, diet, disease, and external factors (e.g., chemotherapy and ionizing radiation) can alter sphingolipid metabolism. When in balance, bone tissue function and structure are maintained. However, when sphingolipid levels, including sphingomyelin, ceramide, aSMase, and S1P, are either up- or downregulated, this can result in, for example, osteoporosis, fragility fractures, inflammation, Paget’s disease, osteoarthritis, rheumatoid arthritis, and spondyloarthritis.

Figure 4

A schematic demonstrating the known effects of ceramides, C1P, sphingomyelin, aSMase, and S1P to the key cells within bone. The effect of physiological, increased, and decreased levels of each sphingolipid are described. Representative chemical structures are presented. The ↑ arrow indicates sphingolipid, biomolecule, cellular, or tissue upregulation, while the ↓ arrow highlights their downregulation.

Figure 5

Pathogenic bacteria are able to adhere, engage, enter, and hijack host cell responses via the sphingolipid pathway. In addition to S. aureus, P. aeruginosa, and E. coli, Helicobacter pylori [274], Neisseria meningitis [275,276], Clostridium botulinum [277,278], Mycobacterium tuberculosis [279,280], Chlamydia psittaci [281], Bacillus cereus [282], Burkolderia pseudomallei and Burkholderia thailandensis [283,284], and Legionella pneumophila [285] are pathogens able to infect bone or that have been reported within the bone marrow. Chlamydia trochomatis is a notorious pathogen able to avoid destruction and persist within host cells [286], and is associated with reactive RA [287]. These bacteria target host cell sphingolipid enzymes either directly (red) or indirectly (green). Image adapted from Rolando et al. [266].