Circadian disruption by shifting the light‐dark cycle negatively affects bone health in mice

Abstract

The past decade, it has become evident that circadian rhythms within metabolically active tissues are very important for physical health. However, although shift work has also been associated with an increased risk of fractures, circadian rhythmicityhas not yet been extensively studied in bone. Here, we investigated which genes are rhythmically expressed in bone, and whether circadian disruption by shifts in lightdark cycle affects bone turnover and structure in mice. Our results demonstrate 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) in bone. Weekly alternating lightdark cycles disrupted rhythmic clock gene expression in bone and caused a reduction in plasma levels of procollagen type 1 amino-terminal propeptide (P1NP) and tartrate-resistant acidic phosphatase (TRAP), suggestive of a reduced bone turnover.These effects coincided with an altered trabecular bone structure and increased cortical mineralization after 15 weeks of light-dark cycles, which may negatively affect

Chronobiology and Chronotherapy of Osteoporosis

“…We and others have demonstrated that the clock genes Bmal1 , Clock , Per1 , Per2 , Cry1 , and Reverba all exhibit diurnal expression patterns in murine calvaria and long bones, ( 40–42 ) indicating that circadian rhythms within bone are indeed maintained through the cell‐autonomous molecular clock. Rhythmic clock gene expression has been detected in cultured osteoclasts ( 42,43 ) as well as osteoblasts, ( 44–46 ) but it is not yet known whether different cell types within bone demonstrate differential expression patterns of clock genes in vivo.…”

“…(48) Various genes involved in osteoclast activity (eg, Ctsk, Nfatc, Rankl, Opg) show potent diurnal expression patterns in bone, (42,43,49) while the osteoblast markers Runx2 and Col1a1 were found not to be rhythmic. (40) However, as Runx2 is mostly involved in osteoblast differentiation (50) and Col1a1 lacks specificity for osteoblasts, (51) this does not necessarily preclude rhythmic osteoblast activity. Genetic disruption of clock genes (52)(53)(54) as well as environmental circadian disruption through shifting light/dark cycles (40) have been shown to affect bone mass in mice, stressing the importance of circadian rhythm in bone remodeling for maintaining skeletal integrity.…”

“…( 40 ) However, as Runx2 is mostly involved in osteoblast differentiation ( 50 ) and Col1a1 lacks specificity for osteoblasts, ( 51 ) this does not necessarily preclude rhythmic osteoblast activity. Genetic disruption of clock genes ( 52–54 ) as well as environmental circadian disruption through shifting light/dark cycles ( 40 ) have been shown to affect bone mass in mice, stressing the importance of circadian rhythm in bone remodeling for maintaining skeletal integrity.…”

“…We have recently demonstrated that repeated shifts in light/dark cycle in mice, as a way to mimic human shift work, reduces markers of bone remodeling (ie, P1NP and CTX) and alters the material and structural properties of bone. ( 40 ) In addition, continuous light exposure has been shown to diminish bone volume and density in mice. ( 107 ) This could be the result of a disrupted circadian clock in combination with sleep deprivation, as sleep duration positively correlates to bone stiffness in humans, ( 108 ) and short sleep is associated with low bone mineral density.…”

Loss of glucocorticoid rhythm induces an osteoporotic phenotype in female mice

“…Bone health is also dependent on a regular day–night rhythm (Winter et al., 2021 ), as reflected in the association between chronic circadian disruption through shift work and osteoporosis in humans (Feskanich et al., 2009 ; Quevedo & Zuniga, 2010 ). We have recently demonstrated that shifting light–dark cycles negatively affects bone health in mice (Schilperoort et al., 2020 ), demonstrating a causal relationship between circadian disruption and bone abnormalities. However, it is currently unknown whether a disrupted GC rhythm, which is also observed with increasing age (Van Cauter et al., 1996 ) and GC therapy (Spies et al., 2014 ), could underlie these effects.…”