Abstract
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. 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. 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. 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. 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. 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. Most importantly however, none of the skeletal parameters assessed by μCT, histomorphometry and serum analyses were significantly influenced by additional S1P3 deficiency. 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. Since S1P receptors are considered excellent drug targets, it is now required to screen for the impact of other family members on bone formation.
Highlights
As evidenced by contact X-ray, 3 weeks old Sgpl1-deficient mice displayed a clear skeletal phenotype, i.e. reduced skeletal growth and increased bone mass, which was apparently unaffected by additional S1P3 deficiency (Fig 1E)
We applied undecalcified histology, where we analyzed 3 weeks old male and female groups of mice. In both genders we observed a significant increase of the trabecular bone mass in spine sections of Sgpl1-deficient mice, regardless of the S1pr3 genotype (Fig 2A)
Its synthesis depends on the activity of sphingosine kinases
Summary
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 [1]. S1P3 does not cause increased bone formation in Sgpl1-deficient mice. The disease is caused by a relative increase of bone resorption, mediated by osteoclasts, over bone formation, mediated by osteoblasts [2]. The treatment of osteoporosis can either be achieved by blocking differentiation or activity of osteoclasts, i.e. anti-resorptive treatment, and/or by activating bone formation by osteoblasts, i.e. osteoanabolic treatment [3]. Whereas cost-effective anti-resorptives are already available, there is still a need to establish better osteoanabolic treatment options. Since long-term blockade of osteoclasts can negatively impact bone matrix quality, stimulating bone formation is principally the preferable way to treat osteoporotic patients
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