Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification

Morita, Kozo; Miyamoto, Takeshi; Fujita, Nobuyuki; Kubota, Yoshiaki; Ito, Keisuke; Takubo, Keiyo; Miyamoto, Kana; Ninomiya, Ken; Suzuki, T.; Iwasaki, Ryuichiro; Yagi, Mitsuru; Takaishi, Hironari; Toyama, Yoshiaki; Suda, Toshio

doi:10.1084/jem.20062525

Cited by 189 publications

(159 citation statements)

References 32 publications

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“…Structural proteins: aggrecan (Acan) (Inada et al, 1999), Col2a1 (de Frutos et al, 2007), Col10a1 (de Frutos et al, 2007), Mmp9 and Mmp13 (Mmp9/13) (Inada et al, 1999), and Spp1 (Inada et al, 1999). Others: Hdac4 (Vega et al, 2004), Sik3 (Sasagawa et al, 2012) and reactive oxygen species (ROS) (Morita et al, 2007). For a comprehensive review of the expression pattern of BMP and TGFβ ligands and receptors, see Minina et al (2005).…”

Section: Tgfβ Signaling In Chondrogenesismentioning

confidence: 99%

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

2015

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Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from mesenchymal progenitor cells to their terminal maturation into hypertrophic chondrocytes. Here, we review how multiple signaling molecules, mechanical signals and morphological cell features are integrated to activate a set of key transcription factors that determine and regulate the genetic program that induces chondrogenesis and chondrocyte differentiation. Moreover, we describe recent findings regarding the roles of several signaling pathways in modulating the proliferation and maturation of chondrocytes in the growth plate, which is the 'engine' of bone elongation.

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Section: Tgfβ Signaling In Chondrogenesismentioning

confidence: 99%

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

2015

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“…12 In addition, chondrocytes undergoing terminal differentiation inexorably progress toward apoptosis, and elevation of reactive oxygen species (ROS) level is probably a major mechanism governing this process. 13 It is now well recognized that those by-products of cellular oxidative metabolism can activate certain signaling pathways. Indeed, increased ROS level during chondrocyte differentiation has been found to activate ERK and p38 MAPK, resulting in chondrocyte hypertrophy 13 (Figure 1).…”

Section: Overview Of the P38 Mapk Signaling Pathwaymentioning

confidence: 99%

“…13 It is now well recognized that those by-products of cellular oxidative metabolism can activate certain signaling pathways. Indeed, increased ROS level during chondrocyte differentiation has been found to activate ERK and p38 MAPK, resulting in chondrocyte hypertrophy 13 (Figure 1).…”

Section: Overview Of the P38 Mapk Signaling Pathwaymentioning

confidence: 99%

Focus on the p38 MAPK signaling pathway in bone development and maintenance

2015

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The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated in response to a wide range of extracellular signals. As a consequence, it can generate many different biological effects that depend on the stimulus and on the activated cell type. Therefore, this pathway has been found to regulate many aspects of tissue development and homeostasis. Recent work with the aid of genetically modified mice has highlighted the physiological functions of this pathway in skeletogenesis and postnatal bone maintenance. In this review, emphasis is given to the roles of the p38 MAPK pathway in chondrocyte, osteoblast and osteoclast biology. In particular, we describe the molecular mechanisms of p38 MAPK activation and downstream targets. The requirement of this pathway in physiological bone development and homeostasis is demonstrated by the ability of p38 MAPK to regulate master transcription factors controlling geneses and functions of chondrocytes, osteoblasts and osteoclasts.

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“…Attempts to identify the required stimuli to drive the formation of permanent articular cartilage have been largely unsuccessful to date. Recent studies suggested that oxygen levels might play a role in driving hypertrophic differentiation (14,15). Interestingly, in the cartilage anlage, permanent articular cartilage is formed under hypoxic conditions, whereas hypertrophic differentiation of cartilage and subsequent endochondral ossification are associated with vascular invasion and, consequently, much higher levels of oxygen.…”

mentioning

confidence: 99%

Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate

Leijten¹,

Georgi²,

Teixeira³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

114

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Actively steering the chondrogenic differentiation of mesenchymal stromal cells (MSCs) into either permanent cartilage or hypertrophic cartilage destined to be replaced by bone has not yet been possible. During limb development, the developing long bone is exposed to a concentration gradient of oxygen, with lower oxygen tension in the region destined to become articular cartilage and higher oxygen tension in transient hypertrophic cartilage. Here, we prove that metabolic programming of MSCs by oxygen tension directs chondrogenesis into either permanent or transient hyaline cartilage. Human MSCs chondrogenically differentiated in vitro under hypoxia (2.5% O 2 ) produced more hyaline cartilage, which expressed typical articular cartilage biomarkers, including established inhibitors of hypertrophic differentiation. In contrast, normoxia (21% O 2 ) prevented the expression of these inhibitors and was associated with increased hypertrophic differentiation. Interestingly, gene network analysis revealed that oxygen tension resulted in metabolic programming of the MSCs directing chondrogenesis into articular-or epiphyseal cartilage-like tissue. This differentiation program resembled the embryological development of these distinct types of hyaline cartilage. Remarkably, the distinct cartilage phenotypes were preserved upon implantation in mice. Hypoxia-preconditioned implants remained cartilaginous, whereas normoxia-preconditioned implants readily underwent calcification, vascular invasion, and subsequent endochondral ossification. In conclusion, metabolic programming of MSCs by oxygen tension provides a simple yet effective mechanism by which to direct the chondrogenic differentiation program into either permanent articular-like cartilage or hypertrophic cartilage that is destined to become endochondral bone.tissue engineering | chondral defects | skeletogenesis | cell therapy | regenerative medicine

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Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification

Cited by 189 publications

References 32 publications

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation

Focus on the p38 MAPK signaling pathway in bone development and maintenance

Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate

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