Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways

Ogawa, Hiroyasu; Kozhemyakina, Elena; Hung, Han-Hwa; Grodzinsky, Alan J.; Lassar, Andrew B.

doi:10.1101/gad.231969.113

Cited by 121 publications

(125 citation statements)

References 45 publications

(73 reference statements)

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“…These results strongly suggest that FSS activates the cAMP-PKA-CREB signaling pathway, which results in upregulation of the expression of PlGF. Activation of the cAMP-PKA-CREB pathway by FSS has been observed in diverse cell types, including chondrocytes, 39 osteocytes, 32 and hematopoietic stem cells. 22 Diaz et al 22 showed that the effects of FSS on hematopoiesis are mediated, in part, by a cascade that involves calcium efflux and stimulation of the PGE2/cAMP/PKA signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP–PKA Signaling Pathway

et al. 2016

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Abstract-The effects of fluid shear stress (FSS) on the human syncytiotrophoblast and its biological functions have never been studied. During pregnancy, the syncytiotrophoblast is the main source of placental growth factor (PlGF), a proangiogenic factor involved in the placental angiogenesis and the vascular adaptation to pregnancy. The role of FSS in regulating PlGF expression in syncytiotrophoblasts is unknown. We investigated the impact of FSS on the production and secretion of the PlGF by the human syncytiotrophoblasts in primary cell culture. Laminar and continuous FSS (1 dyn cm −2) was applied to human syncytiotrophoblasts cultured in a parallel-plate flow chambers. Secreted levels of PlGF, sFlt-1 (soluble fmslike tyrosin kinase-1), and prostaglandin E2 were tested by immunologic assay. PlGF levels of mRNA and intracellular protein were examined by RT-PCR and Western blot, respectively. Intracellular cAMP levels were examined by timeresolved fluorescence resonance energy transfer cAMP accumulation assay. Production of cAMP and PlGF secretion was significantly increased in FSS conditions compared with static conditions. Western blot analysis of cell extracts exposed to FSS showed an increased phosphorylation of protein kinase A substrates and cAMP response element-binding protein on serine 133. FSS-induced phosphorylation of cAMP response element-binding protein and upregulation of PlGF were prevented by inhibition of protein kinase A with H89 (3 μmol/L). FSS also triggers intracellular calcium flux, which increases the synthesis and release of prostaglandin E2. The enhanced intracellular cAMP in FSS conditions was blocked by COX1/COX2 (cyclooxygenase) inhibitors, suggesting that the increase in prostaglandin E2 production could activate the cAMP/protein kinase A pathway in an autocrine/paracrine fashion. FSS activates the cAMP/protein kinase A pathway leading to upregulation of PlGF in human syncytiotrophoblast.

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Section: Discussionmentioning

confidence: 99%

Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP–PKA Signaling Pathway

et al. 2016

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“…Many different signaling modules can activate PKA, including prostaglandins (e.g., PGE 2 ) through the prostanoid receptor ; inflammatory cytokines through interferon signaling (Liu et al, 2004), calcium flux, purinergic ( Jing et al; accompanying paper); and -adrenergic signaling. Because of recent evidence suggesting that PGE 2 is synthesized in response to shear stress (Cherian et al, 2003;Ogawa et al, 2014), and the proposed role of PGE 2 in embryonic hematopoiesis ), PGE 2 is a candidate upstream of PKA for the exploration of shear stress-mediated signaling (Diaz et al; accompanying paper). Indeed, PGE 2 can up-regulate BMP4 in human CD34 + cord blood cells (Goessling et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of protein kinase A (PKA) and its downstream target cAMP response element-binding protein (CREB) by exogenous shear stress has been observed in diverse cell types, including chondrocytes and osteocytes (Cherian et al, 2003;Ogawa et al, 2014). The classic mechanism of PKA activation involves the binding of a ligand to a G proteincoupled receptor and activation of adenylyl cyclase, which converts ATP into the second messenger cyclic AMP (cAMP).…”

Section: Genomic Binding and Interaction Of Creb In K562 Cellsmentioning

confidence: 99%

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

Kim¹,

Nakano²,

Das³

et al. 2015

J Cell Biol

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Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aortagonad-mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)-cAMP response elementbinding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA-CREB and BMP pathways in isolated AGM VEcadherin + cells from mid-gestation embryos, we demonstrate that PKA-CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA-CREB-BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-tohematopoietic transition.

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“…Lubricin coating was reduced on the articular cartilage surface in meniscectomized sheep [78]. The intensive mechanical loading of knee joint, like running, induce Prg4 expression in the superficial zone of articular cartilage in mice [79]. The maximum Prg4-expressing articular cartilage progenitors occurred in the region of knee joints that experience the highest levels of mechanical loading, and thus lie in the central domains of the condyles [79].…”

Section: Lubricin (Prg4)mentioning

confidence: 99%

“…The intensive mechanical loading of knee joint, like running, induce Prg4 expression in the superficial zone of articular cartilage in mice [79]. The maximum Prg4-expressing articular cartilage progenitors occurred in the region of knee joints that experience the highest levels of mechanical loading, and thus lie in the central domains of the condyles [79]. In the current study, less invasive MMx may have caused more expression of lubricin in lateral articular cartilage of femur and tibia ( Figure 13B1) and in medial articular cartilage of femur only ( Figure 13B2).…”

Section: Lubricin (Prg4)mentioning

confidence: 99%

A Less Invasive Approach of Medial Meniscectomy in Rat: A Model to Target Early or Less Severe Human Osteoarthritis

Juneja¹,

Ventura²,

Jay³

et al. 2016

J Arthritis

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Objectives: The existing medial meniscectomy (MMx) procedure in rodents involves transection of MCL and wide opening of the knee capsule followed by meniscus transection that results into articular cartilage degeneration and causes significant changes in subchondral bone at specific post-MMx period. These animals serve as experimental osteoarthritis (OA) models.Structurally, knee is very complex. There may be a need to uncouple articular cartilage degenerative changes from subchondral bone degenerative changes in experimental OA models. Therapeutical drugs/agents, designed to treat articular cartilage degenerative changes of OA knee, may not be effective to treat subchondral bone degenerative changes or vice versa.The purpose of the study was to modify the existing MMx procedure to a less invasive procedure so that it causes only articular cartilage degenerative OA changes and no subchondral bone changes. This will serve as an early OA model to target degenerative changes in articular cartilage in human.Methods: Ten 8-9 weeks old male athymic nude rats underwent less invasive MMx on right knee; the left knee served as unoperated control. The surgery involved no transection of MCL and opening of knee capsule wide. The medial meniscus was pulled out from a slit made on the medial aspect of the knee capsule, and was transected. At 10 weeks post-MMx, animals were sacrificed and knees were assessed. Results:There was no significant alteration in bone strength parameters (BV/TV, Tb.Th, Tb.Sp, Tb.N, Tb.Pf, cortical wall thickness) in subchondral bone in the less invasive MMx knee as analyzed by μCT. X-ray radiography did not indicate the presence of any osteophyte at the knee margins. On the other hand, the less invasive MMx caused degenerative changes in articular cartilage as follows: fibrillation and thinning in the medial tibia; narrowing of medial knee joint; reduced proteoglycans shown by safranin-O staining; decreased metachromasia by PSR staining; alteration in collagen fibril thickness under cross-polarization light. Immunohistochemical expression was reduced (COL-II, aggrecan), increased (NITEGE, Col2-3/4m, COL-X, and MMP13) or imbalanced (lubricin) in articular cartilage thickness of less invasive MMx knee. Conclusion:The less invasive MMx procedure, in rat, can be a model for early or less severe human OA due to articular cartilage degenerative changes only and with no subchondral bone degenerative changes in the knee synovial joint. The therapeutical drugs/agents designed to repair articular cartilage may be suitable for this model and may lead to treatment of early or less severe human OA.Citation: Juneja SC, Ventura M, Jay GD, Veillette C (2016) A Less Invasive Approach of Medial Meniscectomy in Rat: A Model to Target Early or Less Severe Human Osteoarthritis. J Arthritis 5: 193. doi:10.4172/2167-7921.1000193 Page 2 of 17 In rat and mouse, MMx surgery is usually conducted first by transecting the medial collateral ligament (MCL) fully or partially followed by wide opening of the knee capsule, ...

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Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways

Cited by 121 publications

References 45 publications

Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP–PKA Signaling Pathway

Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP–PKA Signaling Pathway

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

A Less Invasive Approach of Medial Meniscectomy in Rat: A Model to Target Early or Less Severe Human Osteoarthritis

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