Decreased Sensory Responses in Osteocalcin Null Mutant Mice Imply Neuropeptide Function

Abstract

Osteocalcin, the most abundant member of the family of extracellular mineral binding gamma-carboxyglutamic acid proteins is synthesized primarily by osteoblasts. Its affinity for calcium ions is believed to limit bone mineralization. Several of the numerous hormones that regulate synthesis of osteocalcin, including glucocorticoids and parathyroid hormone, are also affected by stressful stimuli that require energy for an appropriate response. Based on our observations of OC responding to stressful sensory stimuli, the expression of OC in mouse and rat sensory ganglia was confirmed. It was thus hypothesized that the behavioral responses of the OC knockout mouse to stressful sensory stimuli would be abnormal. To test this hypothesis, behaviors related to sensory aspects of the stress response were quantified in nine groups of mice, aged 4-14 months, comparing knockout with their wild-type counterparts in six distinctly different behavioral tests. Resulting data indicated the following statistically significant differences: open field grooming frequency following saline injection, wild-type > knockout; paw stimulation with Von Frey fibers, knockout < wild-type; balance beam, knockout mobility < WT; thermal sensitivity to heat (tail flick), knockout < wild-type; and cold, knockout < wild-type. Insignificant differences in hanging wire test indicate that these responses are unrelated to reduced muscle strength. Each of these disparate environmental stimuli provided data indicating alterations of responses in knockout mice that suggest participation of osteocalcin in transmission of information about those sensory stimuli.

Altered Ethanol Consumption in Osteocalcin Null Mutant Mice

“…Mice were evaluated for behavior in the light/dark box, open field, and on a 4°C cold plate. These data were reported previously (Patterson-Buckendahl, Sowinska et al 2012). Following these tests, we evaluated taste preferences for saccharin, capsaicin, and menthol, for which there were no significant genotypic differences (data not shown).…”

“…Furthermore, KO could be less sensitive to those prior conditions such that their drinking was less affected, or they might be less sensitive to intoxication resulting from the ETOH consumption. We have previously documented decreased sensitivity by KO in response to varous physical stimuli, including injections (Patterson-Buckendahl, Sowinska et al 2012).…”

New insights into the biology of osteocalcin

“…Routine handling of the osteocalcin null mice suggested that cognition in the mutant mice was impaired relative to control littermates, and more formal behavioral testing revealed an increase in behaviors associated with anxiety and depression (64). A previous study had indicated that osteocalcin is produced in the brain and might function as a neuropeptide (65). However, work by Oury and colleagues (64) demonstrated that circulating osteocalcin crosses the blood-brain barrier and acts in the brainstem, midbrain, and hippocampus to influence the synthesis of several neurotransmitters that favor learning and memory formation.…”

The potent anti-inflammatory effect of Guilu Erxian Glue extracts remedy joint pain and ameliorate the progression of osteoarthritis in mice

“…Guilu Erxian Glue (GEG), which comprises four major components, Testudinis Plastrum , Cornu Cervi , Lycii Fructus , and Ginseng Radix , is a Chinese herbal remedy that has long-lasting favorable effects on aging, perimenopausal syndrome, and degenerative joint diseases in Asia [ 23 – 25 ]. Recent studies have also mentioned that GEG can stimulate the secretion of IGF-1 in osteoblasts and attenuate the bone resorption activity of osteoclasts in vitro [ 26 ], inhibit the formation of osteoclasts and bone pits in rats [ 27 ], and decrease articular pain and increase muscle strength in elderly men with knee OA [ 28 ]. However, knowledge about the mechanisms responsible for the beneficial effects of GEG in OA is limited.…”