ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 OC12.1 | DOI: 10.1530/endoabs.63.OC12.1

Weekly shifts in light-dark cycle disrupt circadian clock gene expression in bone and reduce bone turnover

Maaike Schilperoort1,2, Nathalie Bravenboer1,3, Jan Kroon1,2, Joann Lim2, Leo van Ruyven4, Patrick Rensen1,2, Sander Kooijman1,2 & Elizabeth Winter1,2,3

1Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands; 2Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands; 3Department of Internal Medicine, Center for Bone Quality, Leiden University Medical Center, Leiden, Netherlands; 4Department of Functional Anatomy, Academic Centre for Dentistry, Amsterdam, Netherlands.

The past decade, epidemiological studies have associated disturbances of the biological clock, as occurs in shift work, with low bone mineral density and increased fracture risk. As a large part of the working population participates in shift work (e.g. almost 30% of workers in the U.S.), this demonstrates the need for further research on the risk of skeletal disorders associated with circadian disturbances. In this study, we aimed to investigate to what extent rhythmicity exists in bone, and whether circadian disruption by weekly shifts in light-dark cycle affects bone turnover and structure in mice. To evaluate whether gene expression in bone is rhythmic, tibiae were collected from mice every 6 hours over a 24 hour period (n=9/timepoint). In these bones, we found diurnal expression patterns of clock genes (Rev-erbα, Bmal1, Per1, Per2, Cry1, Clock), as well as genes involved in osteoclastogenesis, osteoclast proliferation and function (Rankl, Opg, Ctsk) and osteocyte function (c-Fos). To study the importance of this rhythm for bone health, mice were subjected to either normal light-dark cycles or weekly 12 hour shifts in light-dark cycle for 16 weeks (n=8/group). Weekly shifts resulted in a disruption of clock gene expression in bone (i.e. reversed rhythm of Rev-erbα (P<0.001) and Cry1 (P<0.01), and attenuated rhythm of Bmal1 (P<0.001) and Clock (P<0.05) three days after a shift), and a reduction in plasma levels of procollagen type 1 amino-terminal propeptide (P1NP, −22.4%; P<0.05) and tartrate-resistant acidic phosphatase (TRAP; −19.9%; P<0.01), suggestive of a reduced bone formation and bone resorption, respectively. Moreover, shifts in light-dark cycle significantly altered trabecular bone structure as determined by micro-CT, and seemed to reduce bone length and weight, consistent with impaired bone growth. Collectively, these results suggest that circadian rhythm is important for bone health, and that circadian disruption negatively affects bone turnover markers and bone structure.

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