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Review
. 2024 Mar 14;13(6):512.
doi: 10.3390/cells13060512.

Hypoxic Conditions Modulate Chondrogenesis through the Circadian Clock: The Role of Hypoxia-Inducible Factor-1α

Krisztián Zoltán Juhász  1 , Tibor Hajdú  1 , Patrik Kovács  1 , Judit Vágó  1 , Csaba Matta  1 , Roland Takács  1
Affiliations
Review

Hypoxic Conditions Modulate Chondrogenesis through the Circadian Clock: The Role of Hypoxia-Inducible Factor-1α

Krisztián Zoltán Juhász et al. Cells. .

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a heterodimer transcription factor composed of an alpha and a beta subunit. HIF-1α is a master regulator of cellular response to hypoxia by activating the transcription of genes that facilitate metabolic adaptation to hypoxia. Since chondrocytes in mature articular cartilage reside in a hypoxic environment, HIF-1α plays an important role in chondrogenesis and in the physiological lifecycle of articular cartilage. Accumulating evidence suggests interactions between the HIF pathways and the circadian clock. The circadian clock is an emerging regulator in both developing and mature chondrocytes. However, how circadian rhythm is established during the early steps of cartilage formation and through what signaling pathways it promotes the healthy chondrocyte phenotype is still not entirely known. This narrative review aims to deliver a concise analysis of the existing understanding of the dynamic interplay between HIF-1α and the molecular clock in chondrocytes, in states of both health and disease, while also incorporating creative interpretations. We explore diverse hypotheses regarding the intricate interactions among these pathways and propose relevant therapeutic strategies for cartilage disorders such as osteoarthritis.

Keywords: HIF-1; chondrogenesis; circadian clock; hypoxia; osteoarthritis; transcription factor.

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Conflict of interest statement

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Molecular machinery of the circadian clock in chondrocytes. The circadian oscillator consists of two interconnected TTFLs. In the core loop, the CLOCK/BMAL1 heterodimer induces E-box-mediated transcription of PER and CRY, the negative regulators. PER and CRY proteins, in turn, repress E-box-mediated transcription. CLOCK and BMAL1 also control the expression of RORs and REV-ERB in the auxiliary loop, which modulate BMAL1 mRNA levels. The rhythmic activity of the clock components also determines the expression of clock-controlled genes (CCGs). Green lines indicate stimulatory (positive), whereas red lines indicate inhibitory (negative) effects. See abbreviations in text. Created with BioRender.com.
Figure 2
Figure 2
Schematic illustration of HIF-1α signaling in chondrogenesis and in mature chondrocytes. Please note that the pathways shown in the figure are not exhaustive. See abbreviations in text. Created with BioRender.com.
Figure 3
Figure 3
Integration of hypoxia signaling and the molecular circadian clock. This schematic illustration highlights the identified interaction sites between hypoxia signaling pathways and the molecular circadian clock in a hypothetical developing chondrocyte. The intertwining of these regulatory networks suggests a complex interplay, influencing various cellular processes and contributing to the coordination of responses to both hypoxia and circadian cues. Please note that the molecular components of pathways shown in the figure are not exhaustive. Green lines indicate stimulatory (positive), whereas red lines indicate inhibitory (negative) effects. Connections with unspecified effects are shown with grey lines. Arrowheads indicate directionality (where relevant). Question marks indicate unconfirmed (hypothetical) connections. See abbreviations in text. Created with BioRender.com.
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