Deficiency of sphingosine-1-phosphate receptor 3 does not affect the skeletal phenotype of mice lacking sphingosine-1-phosphate lyase.

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.

Differential effects of Calca-derived peptides in male mice with diet-induced obesity.

Key metabolic hormones, such as insulin, leptin, and adiponectin, have been studied extensively in obesity, however the pathophysiologic relevance of the calcitonin family of peptides remains unclear. This family includes calcitonin (CT), its precursor procalcitonin (PCT), and alpha calcitonin-gene related peptide (αCGRP), which are all encoded by the gene Calca. Here, we studied the role of Calca-derived peptides in diet-induced obesity (DIO) by challenging Calcr-/- (encoding the calcitonin receptor, CTR), Calca-/-, and αCGRP-/- mice and their respective littermates with high-fat diet (HFD) feeding for 16 weeks.

Parathyroid hormone induces expression and proteolytic processing of Rankl in primary murine osteoblasts.

Rankl, the major pro-osteoclastogenic cytokine, is synthesized as a transmembrane protein that can be cleaved by specific endopeptidases to release a soluble form (sRankl). We have previously reported that interleukin-33 (IL-33) induces expression of Tnfsf11, the Rankl-encoding gene, in primary osteoblasts, but we failed to detect sRankl in the medium. Since we also found that PTH treatment caused sRankl release in a similar experimental setting, we directly compared the influence of the two molecules.

No obvious phenotypic abnormalities in mice lacking the Pate4 gene.

We have previously reported that the hormone calcitonin (CT) negatively regulates bone formation by inhibiting the release of sphingosine-1-phosphate from bone-resorbing osteoclasts. In the context of this study we additionally observed that CT repressed the expression of Pate4, encoding the secreted protein caltrin/Svs7, in osteoclasts from wildtype mice. To assess a possible function of Pate4 in bone remodeling, we utilized commercially available embryonic stem cells with a targeted Pate4 allele to generate Pate4-deficient mice.

Immediate effects of retinoic acid on gene expression in primary murine osteoblasts.

Consistent with clinical observations demonstrating that hypervitaminosis A is associated with increased skeletal fracture risk, we have previously found that dietary retinol deprivation partially corrects the bone mineralization defects in a mouse model of X-linked hypophosphatemic rickets. That retinol-dependent signaling pathways impact the skeleton is further supported by various findings demonstrating a negative influence of retinoic acid (RA) on bone-forming osteoblasts. We hypothesized that RA would directly regulate the expression of specific target genes in osteoblasts, and we aimed to identify these by genome-wide expression analyses.

Increased osteoclastogenesis in mice lacking the carcinoembryonic antigen-related cell adhesion molecule 1.

Alterations in bone remodeling are a major public health issue, as therapeutic options for widespread bone disorders such as osteoporosis and tumor-induced osteolysis are still limited. Therefore, a detailed understanding of the regulatory mechanism governing bone cell differentiation in health and disease are of utmost clinical importance. Here we report a novel function of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a member of the immunoglobulin superfamily involved in inflammation and tumorigenesis, in the physiologic regulation of bone remodeling.

Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation.