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However, little attention has been paid to the direct effects of caffeine on chondrocytes. Here, we investigated the direct effects of caffeine on chondrocytes of the growth plate<jats:italic>in\u00a0vivo<\/jats:italic>and<jats:italic>in\u00a0vitro<\/jats:italic>using a rapidly growing young rat model, and determined whether they were related to the adenosine receptor signaling pathway. A total of 15 male rats (21\u00a0days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>\u00a0day<jats:sup>\u22121<\/jats:sup>for 4\u00a0weeks. After sacrifice, the tibia processed for the analysis of the long bone growth and proliferation of chondrocytes using tetracycline and BrdU incorporation, respectively. Caffeine\u2010fed animals showed decreases in matrix mineralization and proliferation rate of growth plate chondrocytes compared with the control. To evaluate whether caffeine directly affects chondrocyte proliferation and chondrogenic differentiation, primary rat chondrocytes were isolated from the growth plates and cultured in either the presence or absence of caffeine at concentrations of 0.1\u20131\u00a0m<jats:sc>m<\/jats:sc>, followed by determination of the cellular proliferation or expression profiles of cellular differentiation markers. Caffeine caused significant decreases in extracellular matrix production, mineralization, and alkaline phosphatase activity, accompanied with decreases in gene expression of the cartilage\u2010specific matrix proteins such as aggrecan, type<jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>collagen and type X. Our results clearly demonstrate that caffeine is capable of interfering with cartilage induction by directly inhibiting the synthetic activity and orderly expression of marker genes relevant to chondrocyte maturation. In addition, we found that the adenosine type 1 receptor signaling pathway may be partly involved in the detrimental effects of caffeine on chondrogenic differentiation, specifically matrix production and mineralization, as evidenced by attenuation of the inhibitory effects of caffeine by blockade of this receptor. Thus, our study provides novel information on the integration of caffeine and adenosine receptor signaling during chondrocyte maturation, extending our understanding of the effect of caffeine at a cellular level on chondrocytes of the growth plate.<\/jats:p>","DOI":"10.1111\/joa.12530","type":"journal-article","created":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T06:28:44Z","timestamp":1470205724000},"page":"117-127","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Longitudinal bone growth is impaired by direct involvement of caffeine with chondrocyte differentiation in the growth plate"],"prefix":"10.1111","volume":"230","author":[{"given":"Hyeonhae","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Anatomy &amp; Cell Biology College of Medicine Hanyang University Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Anatomy &amp; 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