AP-1

AP-1 transcription factor complex is a target of signals from both WnT-7a and N-cadherin-dependent cell-cell adhesion complex during the regulation of limb mesenchymal chondrogenesis.

"Wnt signaling [regulates] limb mesenchymal chondrogenesis. We analyzed the molecular mechanism of Wnt-7a inhibition of chondrogenic differentiation by examining the involvement of mitogen-activated protein kinase (MAPK) pathways, i.e., Erk and p38. The combination of Wnt-7a misexpression and Erk inhibition partially recovers Wnt-7a inhibition of chondrogenic differentiation, whereas the combination of Wnt-7a misexpression and p38 inhibition acts in a synergistic chondro-inhibitory fashion. Wnt-7a misexpression has no direct effect on Erk signaling [but] increases the activity of one of the ultimate targets of the MAPK pathway, c-jun, a major component of the activator protein-1 (AP-1) transcription factor complex. Wnt-7a misexpression enhances the activity of an AP-1 promoter-luciferase reporter construct by approximately 2.3-fold in vitro. Misexpression of wild-type N-cadherin in these micromass cultures suppresses the activity of the same AP-1 promoter by approximately 40%, whereas misexpression of an extracellular 390-amino-acid N-terminal deletion mutant of N-cadherin has a stimulatory effect on the AP-1 promoter activity by approximately 2.6-fold. A part of the chondro-inhibitory effect of Wnt-7a misexpression may involve AP-1 transcription factor stimulation. Furthermore, a very tightly regulated level of AP-1 activity is necessary for the process of limb mesenchymal chondrogenesis, and signals from Wnt-ligands (e.g., Wnt-7a), cell adhesion molecules (e.g., N-cadherin), and MAPK pathways (e.g., Erk and p38) are interactively involved in this regulation."

"B-catenin misexpression results in altered expression of c-jun and fra-1[fra1 inhibits chondrogenesis], genes that encode two components of the AP-1 transcription complex."

"Lithium, a Wnt mimetic that acts by inhibiting the activity of a negative regulator of the Wnt signaling pathway, glycogen synthase kinase (GSK)-3b, [increases] the activity of the AP-1 promoter"

"Wnt-7a misexpression significantly stimulated the activity of a cotransfected AP-1 promoter–luciferase reporter construct throughout the process of chondrogenesis, compared to RCAS control cultures"

"Chondrogenesis was increased in cultures expressing N-cadherin at a moderate level (2-fold), whereas cells expressing 4-fold or higher wild-type N-cadherin or the dominant negative N-cadherin construct had an initial, inhibitory effect on BMP-2 stimulation of chondrogenesis"

"Low level of AP-1 promoter activity is necessary for the process of limb mesenchymal chondrogenesis, consistent with our recent finding that a cell-density-dependent, low but steady level of AP-1 activity is required for promoting the chondrogenic potential of the multipotential C3H10T1/2 mesenchymal cell line"

JNK/ERK–AP-1/Runx2 induction “paves the way” to cartilage load-ignited chondroblastic differentiation

"4-day-old female Wistar rats were divided into 2 groups: the first group was fed hard diet (simulating physiologic temporomandibular joint (TMJ) loading), while the second group was fed soft diet (reduced TMJ loading). On day 21 (experiment initiation day − weaning day), biopsies from condyles of both groups were obtained after 6, 12 and 48 h of functional TMJ loading. Immunohistochemical methodology was employed to evaluate the expression levels of pc-Jun, c-Fos{up in LSJL}, JNK2, p-JNK, p-ERK and Runx2 due to alteration in functional load. The protein levels of all the aforementioned molecules were markedly increased in animals fed with the hard diet, throughout the experimental procedure. Functional cartilage loading induces the AP-1 and Runx2 transcription factors through the JNK and ERK MAPK cascades."

"c-Jun accelerates cell-cycle progression and c-Fos enhances cell proliferation and apoptosis"

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

"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. 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{up} 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{up}, Fra-1, Fra-2, c-Jun{up}, and Jun-B{up} 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. Regulation of chondrocyte differentiation through β(2)-AR [is] mediated by ERK1/2 and PKA stimulation of the AP-1 factor Jun-B that inhibits the expression of Sox-6 and Col II."

"β2-AR stimulates PKA phosphorylation of CREB, activating both activator protein-1 (AP-1) factors and the clock gene"

"Rats treated for 4 wk with a selective β2-AR agonist had shortened bone length"

"junB−/−Ubi-junB mice, which have very low levels of Jun-B expression in bone, have shortened growth plates with reduced numbers of proliferative and prehypertrophic chondrocytes"

"Isoproterenol has a modest growth stimulatory effect on growth plate chondrocytes in culture, and it is possible that the stimulation of Jun-B contributed to that increase in growth."<-Isoproterenol is prescription only.