β₂-Adrenergic receptors inhibit the expression of collagen type II in growth plate chondrocytes by stimulating the AP-1 factor Jun-B

Abstract

The sympathetic nervous system can regulate both osteoblast and chondrocyte growth and activity through β(2)-adrenergic receptors (β(2)-AR). We have shown previously that β(2)-AR activate both adenylyl cyclase and mitogen-activated protein kinases ERK1/2 in growth plate chondrocytes prepared from ribs of embryonic E18.5 mice. Here we examined β(2)-AR inhibition of collagen type II (Col II) expression in growth plate chondrocytes and the molecular pathways involved. Stimulation of β(2)-AR by isoproterenol inhibited Col II mRNA and protein levels by ∼50% beginning at 2 h, with both remaining suppressed over 24 h. This inhibition was blocked by propranolol and inhibitors of either MEK1 or PKA. Isoproterenol stimulated an AP-1-luciferase reporter and increased the expression of AP-1 factors c-Fos, Fra-1, Fra-2, c-Jun, and Jun-B but had no effect on Jun-D. Stimulation of AP-1 activity was blocked by inhibitors of MEK1 or PKA. siRNA inhibition of AP-1 factors showed that depletion of only Jun-B attenuated isoproterenol-mediated inhibition of Col II. Transfection with jun-B or c-fos showed selective inhibition of Col II mRNA and a Col II luciferase reporter construct by jun-B. Isoproterenol as well as jun-B overexpression in the chondrocytes also inhibited the expression of Sox-6 mRNA and protein, and depletion of Jun-B abrogated β(2)-AR inhibition of Sox-6. Collectively, these findings demonstrate regulation of chondrocyte differentiation through β(2)-AR mediated by ERK1/2 and PKA stimulation of the AP-1 factor Jun-B that inhibits the expression of Sox-6 and Col II.

Interleukin-1β and tumor necrosis factor-α increase stiffness and impair contractile function of articular chondrocytes

“…Since cytokines make the chondrocytes be in a more contracted state, the cells might not respond well to compressive forces that are supposed to induce cellular deformation and contraction [62]. Besides, both the agonists used in this study have shown catabolic effects: histamine increased MMP-3 and MMP-13 production [63], and isoproterenol inhibits type II collagen expression through β 2 -adrenergic receptors [64]. This further suggested that IL-1β and TNF-α might change the responses of chondrocytes to other catabolic agents, resulting in the activation of corresponding pathways that contribute to OA progression.…”

The brain–joint axis in osteoarthritis: nerves, circadian clocks and beyond

“…However, in vitro and ex vivo studies show that ANS-related neurotransmitters can influence chondrogenesis [42][43][44][45] . A few studies have looked at the role of adrenergic receptors present at the surface of chondrocytes, including in human OA cartilage Indeed, β 2 adrenergic receptors and α 2 adrenergic receptors are both expressed on epiphyseal proliferating chondrocytes [44][45][46][47][48][49] . Adrenaline inhibits the maturation process of growth plate chondrocytes with downregulation of the expression of type II collagen and Sox6 (REFS 42,45).…”

“…A few studies have looked at the role of adrenergic receptors present at the surface of chondrocytes, including in human OA cartilage Indeed, β 2 adrenergic receptors and α 2 adrenergic receptors are both expressed on epiphyseal proliferating chondrocytes [44][45][46][47][48][49] . Adrenaline inhibits the maturation process of growth plate chondrocytes with downregulation of the expression of type II collagen and Sox6 (REFS 42,45). Contradictory results have been reported showing either an upregulation or a downregulation of type X collagen expression with no effect on type II collagen after activation of β 2 adrenergic receptors 44,49 .…”

Norepinephrine Inhibition of Mesenchymal Stem Cell and Chondrogenic Progenitor Cell Chondrogenesis and Acceleration of Chondrogenic Hypertrophy

“…A direct effect of NE, the major neurotransmitter of the sympathetic nervous system, has been demonstrated in primary murine chondrocytes (). However, CPC‐ or MSC‐dependent chondrogenesis in terms of possible unfavorable hypertrophic differentiation characterized by markers such as type X collagen and MMP‐13 has never been studied under the influence of sympathetic neurotransmitters.…”