Bone loss in C57BL/6J-OlaHsd mice, a substrain of C57BL/6J carrying mutated alpha-synuclein and multimerin-1 genes.

The inbred mouse strain C57BL/6 is commonly used for the generation of transgenic mouse and is a well established strain in bone research. Different vendors supply different substrains of C57BL/6J as wild-type animals when genetic drift did not incur any noticeable phenotype. However, we sporadically observed drastic differences in the bone phenotype of "WT" C57BL/6J mice originating from different labs and speculated that these variations are attributable, at least in part, to the variation between C57BL/6J substrains, which is often overlooked. C57BL/6J-OlaHsd is a commonly used substrain that despite a well defined deletion in the alpha-synuclein (Snca) and multimerin-1 (Mmrn1) genes, was reported to display no obvious phenotype and is used as WT control. Here, we compared the bone phenotype of C57BL/6J-OlaHsd (6J-OLA) to C57BL/6J-RccHsd (6J-RCC) and to the original C57BL/6J (6J-JAX). Using µCT analysis, we found that 6J-OLA mice display a significantly lower trabecular bone mass compared to 6J-RCC and 6J-JAX. PCR analysis revealed that both the Snca and Mmrn1 genes are expressed in bone tissue of 6J-RCC animals but not of 6J-OLA mutants, suggesting either one or both genes play a role in bone metabolism. In vitro analysis demonstrated increase in osteoclasts number and decreased osteoblast mineralization in cells derived from 6J-OLA compared with 6J-RCC. Our data may shed light on unexplained differences in basal bone measurements between different research centers and reiterate the importance of specifying the exact substrain type. In addition, our findings describe the physiological role for Mmrn1 and/or Snca in bone remodeling.

Depression and bone mass.

Although it has been repeatedly suggested that low bone mineral density (BMD) is disproportionately prevalent among patients with depressive disorders, so far depression has not been officially acknowledged as a risk factor for osteoporosis. In a recent meta-analysis comparing depressed with nondepressed individuals we report that BMD is lower in depressed than nondepressed subjects. The association between depression and BMD is stronger in women than men, and in premenopausal than postmenopausal women. Only women psychiatrically diagnosed for major depression display significantly low BMD; women diagnosed by self-rating questionnaires do not. Using a mouse model for depression, we demonstrate a causal relationship between depressive-like behavior and bone loss. The depression-induced bone loss is associated with increases in skeletal norepinephrine and serum corticosterone levels. Bone loss, but not the depressive behavior, could be prevented by a beta-blocker. Hence, depression appears as a significant risk factor for low BMD, causing bone loss through stimulation of the sympathetic nervous system.

Regulation of skeletal remodeling by the endocannabinoid system.

Since the discovery of the endocannabinoid system, its presence and involvement have been reported in a handful of biological systems. Recently, the skeleton has been identified as a major endocannabinoid target through both the neuronal CB1 and predominantly peripheral CB2 cannabinoid receptors. CB1 is present in sympathetic nerve terminals in bone, whereas CB2 is expressed in osteoblasts and osteoclasts, the respective bone-forming and -resorbing cells. Furthermore, the skeleton appears as the main system physiologically regulated by CB2. CB2-deficient mice show a markedly accelerated age-related bone loss and the CB2 locus in women is associated with low bone density and osteoporotic fractures. Since activation of CB2 attenuates experimentally induced bone loss by inhibiting bone resorption and stimulating bone formation, and because synthetic cannabinoids are stable and orally available, a therapy based on synthetic CB2 agonists is a promising novel target for antiosteoporotic drug development.