We have previously reported that the hormone calcitonin (CT) mediates a negative influence on bone formation through binding to its receptor (CTR) on osteoclasts. On the other hand, there is increasing evidence for the existence of osteoclast-derived molecules with a positive influence on bone formation, albeit it remains to be established, which of the molecules proposed to be involved in this coupling process are physiologically relevant. In fact, the two most critical regulators of bone resorption, the cytokine RANKL and its decoy receptor OPG, are both produced by osteoblasts, and a change in the ratio of osteoblast-derived RANKL/OPG specifically affects bone resorption. In this regard it is highly relevant that there is evidence for the existence of a molecular crosstalk between osteoblasts and osteoclasts. Moreover, since long-term blockade of osteoclasts can negatively impact bone matrix quality, stimulating bone formation is principally the preferable way to treat osteoporotic patients. Whereas cost-effective anti-resorptives are already available, there is still a need to establish better osteoanabolic treatment options. anti-resorptive treatment, and/or by activating bone formation by osteoblasts, i.e. Therefore, the treatment of osteoporosis can either be achieved by blocking differentiation or activity of osteoclasts, i.e. Since the two bone remodeling cells differ with respect to progenitor cells and mode of action, they are also regulated by different sets of molecules. The disease is caused by a relative increase of bone resorption, mediated by osteoclasts, over bone formation, mediated by osteoblasts. Osteoporosis is one of the most prevalent disorders in the aged population, and skeletal fractures have a high detrimental impact, causing either mortality or reduced quality of life. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the manuscript and its Supporting Information files.įunding: This work was supported by the German Research foundation (AM 103/24-1).
Received: ApAccepted: JPublished: July 17, 2019Ĭopyright: © 2019 Heckt et al. PLoS ONE 14(7):Įditor: Dominique Heymann, Universite de Nantes, FRANCE Since S1P receptors are considered excellent drug targets, it is now required to screen for the impact of other family members on bone formation.Ĭitation: Heckt T, Brylka LJ, Neven M, Amling M, Schinke T (2019) Deficiency of sphingosine-1-phosphate receptor 3 does not affect the skeletal phenotype of mice lacking sphingosine-1-phosphate lyase. Taken together, our findings fully support the concept that S1P is a potent osteoanabolic molecule, although S1P3 is not the sole receptor mediating this influence. Most importantly however, none of the skeletal parameters assessed by μCT, histomorphometry and serum analyses were significantly influenced by additional S1P3 deficiency. At 3 weeks of age, Sgpl1-deficient mice displayed increased trabecular bone mass, which was associated with enhanced osteoclastogenesis and bone resorption, but also with increased bone formation. Consistent with previous reports, the majority of Sgpl1-deficient mice died before or shortly after weaning, and this lethality was not influenced by additional S1P3 deficiency. In the present study we addressed the question, if S1P3 deficiency would also influence the skeletal phenotype of mice lacking S1P-lyase (encoded by Sgpl1), which display markedly increased S1P levels due to insufficient degradation. Moreover, S1pr3, encoding one of the five known S1P receptors (S1P3), was found differentially expressed in osteoblasts, and S1P3 deficiency corrected the moderate high bone mass phenotype of a mouse model (deficient for the calcitonin receptor) with increased S1P release from osteoclasts. We and others have previously identified sphingosine-1-phosphate (S1P) as a bone remodeling coupling factor, which is released by bone-resorbing osteoclasts to stimulate bone formation. Albeit osteoporosis is one of the most prevalent disorders in the aged population, treatment options stimulating the activity of bone-forming osteoblasts are still limited.
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