Clock Genes Influence Gene Expression in Growth Plate and Endochondral Ossification in Mice

Takarada, Takeshi; Kodama, Ayumi; Hotta, Shogo; Mieda, Michihiro; Shimba, Shigeki; Hinoi, Eiichi; Yoneda, Yukio

doi:10.1074/jbc.m112.408963

Cited by 86 publications

(121 citation statements)

References 36 publications

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“…PER and CRY proteins accumulate and multimerize in the cytoplasm during the day, then move back to the nucleus in the evening to inhibit CLOCK and BMAL1 activity, thus inhibiting their own transcription. Previous work identified autonomous cartilage circadian rhythms in mice that became dysregulated with age and upon chronic inflammation (11)(12)(13)(14). Moreover, environmental disruption of circadian rhythms in mice (mimicking chronic jet lag) predisposes knee cartilage to OA-like damage (15), further supporting the idea of an involvement of circadian rhythm disruption in OA development.…”

Section: Introductionmentioning

confidence: 56%

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Dudek¹,

Gossan²,

Yang³

et al. 2015

Journal of Clinical Investigation

164

202

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Section: Introductionmentioning

confidence: 56%

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Dudek¹,

Gossan²,

Yang³

et al. 2015

Journal of Clinical Investigation

164

202

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“…It was previously demonstrated by Takarada et al that global deletion of BMAL1 results in decreased body size and weight and defective chondrogenesis, locomotor ability, and metabolism (11). The same group had also crossed BMAL1-floxed mice with a chondrocyte-specific Col2a1-Cre deleter strain (12) and showed that chondrocyte-specific deletion of BMAL1 results in bone development defects similar to those seen in global KO mice (11). The Dudek et al study (9) complements the previous study by addressing the role of BMAL1 in cartilage homeostasis in adult tissues.…”

Section: Wrist Watches: Cartilage Clocks In Articular Jointsmentioning

confidence: 99%

Chondrocyte clocks make cartilage time-sensitive material

Doody¹,

Bottini²

2015

Journal of Clinical Investigation

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C o m m e n t a r y3 Circadian clocksDiurnal patterns of rest and activity drive a vast array of normal physiological processes, but also affect the activity of acute and chronic diseases (1-4). Indeed, daily patterns of pain and stiffness have been well documented in hands (5), knees (6), and hips (7) of osteoarthritic patients, yet the physiological basis for such patterns is poorly understood. The mammalian circadian clock is a hierarchical system composed of a central clock located in the hypothalamus as well as several peripheral clocks, in which transcriptional activity is regulated by transcription factors brain and muscle Arnt-like proteins 1 and 2 (BMAL1/2) that dimerize with circadian locomotor output cycles kaput (CLOCK) and initiate the transcription of a variety of E-box promoter-containing genes involved in various cellular processes. Two such genes encode CRY and PER, which accumulate in the cytoplasm, enter the nucleus to inhibit BMAL/ CLOCK transcription, and are then degraded to form a complete feedback loop that cycles every 24 hours (8). Wrist watches: cartilage clocks in articular jointsMuch is known of the central clock and its systemic control of peripheral clocks as well as how its disruption affects normal and disease processes, yet it is unclear whether and how individual peripheral clocks play a role in tissue-specific disease. In a study published in this issue of the JCI, Dudek et al. (9) investigate the contribution of cartilage chronobiology to the pathogenesis of osteoarthritis. The same group recently showed that chondrocytes, the cellular component of cartilage, have a cell-autonomous circadian clock (10). In the present study, Dudek et al. confirm the presence of a cartilage clock and study the cartilage-specific effects of the key transcription factor BMAL1. The authors first demonstrate that the expression of BMAL1 protein in chondrocytes of knee cartilage is negatively correlated with the severity of osteoarthritis in humans and with age in mice. This suggests that the loss of clock components during osteoarthritis and normal aging may be intimately linked with cartilage health.In order to isolate the role of BMAL1 within the cartilage clock, the authors used BMAL1-floxed mice crossed with a chondrocyte-specific Col2a1-Cre deleter strain. It was previously demonstrated by Takarada et al. that global deletion of BMAL1 results in decreased body size and weight and defective chondrogenesis, locomotor ability, and metabolism (11). The same group had also crossed BMAL1-floxed mice with a chondrocyte-specific Col2a1-Cre deleter strain (12) and showed that chondrocyte-specific deletion of BMAL1 results in bone development defects similar to those seen in global KO mice (11). The Dudek et al. study (9) complements the previous study by addressing the role of BMAL1 in cartilage homeostasis in adult tissues. Their study of adult cartilage homeostasis in cartilage-specific BMAL1-KO mice was facilitated by a lack of the defects in body weight and bone growth that were observed in the st...

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“…Researchers found that mice lacking the core clock genes, Bmal1 (Bmal1 -/ -), Clock (Clock -/ -), or Per2 (Per2 -/ -), showed early aging symptoms compared with their wild-type littermates [7][8][9], especially the Bmal1 -/ -mice, in which early aging symptoms were more obvious [10]. Studies also found that endochondral ossification was under control by clock genes in chondrocytes [11].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the Circadian Clock Gene Rev-erbα Affects Murine Bone Mesenchymal Stem Cell Proliferation and Osteogenesis

Lin

Chen

et al. 2015

Stem Cells and Development

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Bone mesenchymal stem cell (BMSC) age-related changes include decreased osteogenesis and increased adipogenesis. Rev-erba and the Wnt/b-catenin signaling pathway were known to play important roles in BMSC aging. In this study, we have aimed to elucidate whether Rev-erba and Wnt/b-catenin signaling interact during BMSC proliferation and osteogenesis. Our results showed that Rev-erba expression gradually dropped during BMSC osteogenesis, and overexpression of Rev-erba in BMSCs inhibited cell proliferation and osteogenesis. The inhibition of cell proliferation induced by Rev-erba overexpression was partially reversed when Wnt/bcatenin signaling was activated. These results suggested that Rev-erba could promote BMSC aging and may be the negative regulator during the late stage of osteogenesis. The clock gene Rev-erba and Wnt/b-catenin signaling interact in the regulation of cell proliferation.

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Clock Genes Influence Gene Expression in Growth Plate and Endochondral Ossification in Mice

Cited by 86 publications

References 36 publications

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Chondrocyte clocks make cartilage time-sensitive material

Overexpression of the Circadian Clock Gene Rev-erbα Affects Murine Bone Mesenchymal Stem Cell Proliferation and Osteogenesis

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