Insights into the Role of Circadian Rhythms in Bone Metabolism: A Promising Intervention Target?

Table 1

Summary of circadian and bone phenotypes in clock gene transgenic mice.

Gene	Circadian phenotype	Bone phenotype
CLOCK	CLOCK mutant mice (): long circadian period (26-28h) [80]; CLOCK knockout mice: robust circadian rhythm in locomotor activity [81]	Clock mutant mice: low bone mass [83]
BMAL1	BMAL1-/- mice: impaired locomotor activity [87]	BMAL1 knockout mice: low bone mass [87]
PERs	PER1-deficient mice: disrupted circadian behavioral rhythms [89]; PER2-deficient mice: disrupted circadian behavioral rhythms [89]	PER1-deficient mice: normal bone volume [91]; PER2-deficient mice: normal bone volume [91]; PER2 PAS domain (): normal bone volume [91]; PER1^−/−;: significantly increased bone mass [91]; PER1-/-; PER2-/-: increased bone mass [91]; mice: increased bone volume at 3, 12 and 48 weeks [92]
CRYs	CRY1-deficient mice: circadian period 1 hour shorter than wild type [93, 94]; CRY2-deficient mice: circadian period 1 hour longer than wild type [95]; CRY1/2 double knockout mice: arrhythmic in constant darkness [121]	CRY1-deficient mice: not reported; CRY2-deficient mice: increased bone volume [94]; CRY1/2 double knockout mice: high bone volume [91]
REV-ERBs	REV-ERBα knockout: average period length significantly shorter [122]; REV-ERBβ knockout: no changes in circadian activity rhythms [123]; REV-ERBα/β double knockout: the free running period length in constant darkness was 2.5 hours shorter [123]	REV-ERBα knockout: not reported; REV-ERBβ knockout: not reported; REV-ERBα/β agonist SR9009: suppressed osteoclast formation and ameliorated OVX-induced bone loss [17]
RORs	RORα (sg/sg): shortened period length of the locomotor activity rhythm [102]; RORβ knockout: significant increase in circadian period in constant dark [103]	RORα (sg/sg): osteopenic [104]; RORβ knockout: increase bone mass [108]
DECs	DEC1 knockout: longer circadian period under conditions of constant darkness [109]; DEC2 knockout: no changes in circadian activity rhythms [110]	DEC1 or DEC2 knockout: not reported
DBP	DBP knockout: shorter period [124]	DBP knockout: normal bone volume [120]