Rapid membrane responses to dihydrotestosterone are sex dependent in growth plate chondrocytes

Elbaradie, Khairat; Wang, Yun; Boyan, Barbara D.; Schwartz, Zvi

doi:10.1016/j.jsbmb.2011.12.009

Cited by 16 publications

(10 citation statements)

References 62 publications

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“…Our hypothesis that CaMKII is required for Wnt5a induced activation of PKC is also supported by the observation that CaMKII regulates PLA 2 activity (45). PLA 2 is known to act upstream of PKC in several signaling pathways, including 1α,25(OH) 2 D 3 and dihydrotestosterone (14,51), hence CaMKII influences PKC activity in a PLA 2 -dependent mechanism. Additionally, in agreement with previous findings (14,51), we found that PLA 2 inhibition abolished Wnt5a induced activation of PKC in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Signaling components of the 1α,25(OH)2D3-dependent Pdia3 receptor complex are required for Wnt5a calcium-dependent signaling

Doroudi

Olivares-Navarrete

Hyzy

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Wnt5a and 1α,25(OH)2D3 are important regulators of endochondral ossification. In osteoblasts and growth plate chondrocytes, 1α,25(OH)2D3 initiates rapid effects via its membrane-associated receptor protein disulfide isomerase A3 (Pdia3) in caveolae, activating phospholipase A2 (PLA2)-activating protein (PLAA), calcium/calmodulin-dependent protein kinase II (CaMKII), and PLA2, resulting in protein kinase C (PKC) activation. Wnt5a initiates its calcium-dependent effects via intracellular calcium release, activating PKC and CaMKII. We investigated the requirement for components of the Pdia3 receptor complex in Wnt5a calcium-dependent signaling. We determined that Wnt5a signals through a CaMKII/PLA2/PGE2/PKC cascade. Silencing or blocking Pdia3, PLAA, or vitamin D receptor (VDR), and inhibition of calmodulin (CaM), CaMKII, or PLA2 inhibited Wnt5a-induced PKC activity. Wnt5a activated PKC in Caveolin-1-silenced cells, but methyl-beta-cyclodextrin reduced its stimulatory effect. 1α,25(OH)2D3 reduced stimulatory effects of Wnt5a on PKC in a dose-dependent manner. In contrast, Wnt5a had a biphasic effect on 1α,25(OH)2D3-stimulated PKC activation; 50ng/ml Wnt5a caused a 2-fold increase in 1α,25(OH)2D3-stimulated PKC but higher Wnt5a concentrations reduced 1α,25(OH)2D3-stimulated PKC activation. Western blots showed that Wnt receptors Frizzled2 (FZD2) and Frizzled5 (FZD5), and receptor tyrosine kinase-like orphan receptor 2 (ROR2) were localized to caveolae. Blocking ROR2, but not FZD2 or FZD5, abolished the stimulatory effects of 1α,25(OH)2D3 on PKC and CaMKII. 1α,25(OH)2D3 membrane receptor complex components (Pdia3, PLAA, Caveolin-1, CaM) interacted with Wnt5a receptors/co-receptors (ROR2, FZD2, FZD5) in immunoprecipitation studies, interactions that changed with either 1α,25(OH)2D3 or Wnt5a treatment. This study demonstrates that 1α,25(OH)2D3 and Wnt5a mediate their effects via similar receptor components and suggests that these pathways may interact.

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Section: Discussionmentioning

confidence: 99%

Signaling components of the 1α,25(OH)2D3-dependent Pdia3 receptor complex are required for Wnt5a calcium-dependent signaling

Doroudi

Olivares-Navarrete

Hyzy

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…To put in context the role of L-type VDCCs, a hypothesis was elaborated to explain the role of these channels in dihydrotestosterone (DTH) signalling; showing that DHT regulates growth plate chondrocytes in a sex-specific manner [29]. Upon binding to its 7-TM domaincontaining plasma membrane receptor, DTH was proposed to initiate the phospholipase C (PLC) signalling pathway leading to Ca 2+ release from internal Ca 2+ stores through activation of IP3 signalling; furthermore, Gβγ subunits would induce Ca 2+ influx through L-type VDCCs in resting zone growth plate chondrocytes derived from male rats.…”

Section: Vdccs and The Effects Of Nifedipine/verapamil On Chondrocytesmentioning

confidence: 99%

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

2015

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Chondrocytes, the single cell type in adult articular cartilage, have conventionally been considered to be non-excitable cells. However, recent evidence suggests that their resting membrane potential (RMP) is less negative than that of excitable cells, and they are fully equipped with channels that control ion, water, and osmolyte movement across the chondrocyte membrane. Among calcium-specific ion channels, members of the voltage-dependent calcium channel (VDCC) family are expressed in chondrocytes where they are functionally active. Ltype VDCC inhibitors such as nifedipine and verapamil have contributed to our understanding of the roles of these ion channels in chondrogenesis, chondrocyte signalling, and mechanotransduction. In this narrative review, we discuss published data indicating that VDCC function is vital for chondrocyte health, especially in regulating proliferation and maturation.We also highlight the fact that activation of VDCC function appears to accompany various inflammatory aspects of osteoarthritis (OA) and, based on in vitro data, the application of nifedipine and/or verapamil may be a promising approach for ameliorating OA severity.However, very few studies on clinical outcomes are available regarding the influence of calcium antagonists, which are used primarily for treating cardiovascular conditions in OA patients. This review is intended to stimulate further research on the chondrocyte 'channelome', contribute to the development of novel therapeutic strategies, and facilitate the retargeting and repositioning of existing pharmacological agents currently used for other comorbidities for the treatment of OA.

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“…, only in males. PI-PLC was required for the DHT–dependent activation of PKC [400] as evidenced by the effect of U-73122. The eotaxin-dependent matrix metalloproteinase secretion in human chondrosarcoma cell line SW1353 is regulated by a PI-PLC-PKC cascade and c-Jun N -terminal kinase/MAP kinase pathways [401].…”

Section: Pi-specific Phospholipase Cmentioning

confidence: 99%

Phospholipases of Mineralization Competent Cells and Matrix Vesicles: Roles in Physiological and Pathological Mineralizations

Mébarek

Abousalham

Magne

et al. 2013

IJMS

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The present review aims to systematically and critically analyze the current knowledge on phospholipases and their role in physiological and pathological mineralization undertaken by mineralization competent cells. Cellular lipid metabolism plays an important role in biological mineralization. The physiological mechanisms of mineralization are likely to take place in tissues other than in bones and teeth under specific pathological conditions. For instance, vascular calcification in arteries of patients with renal failure, diabetes mellitus or atherosclerosis recapitulates the mechanisms of bone formation. Osteoporosis—a bone resorbing disease—and rheumatoid arthritis originating from the inflammation in the synovium are also affected by cellular lipid metabolism. The focus is on the lipid metabolism due to the effects of dietary lipids on bone health. These and other phenomena indicate that phospholipases may participate in bone remodelling as evidenced by their expression in smooth muscle cells, in bone forming osteoblasts, chondrocytes and in bone resorbing osteoclasts. Among various enzymes involved, phospholipases A1 or A2, phospholipase C, phospholipase D, autotaxin and sphingomyelinase are engaged in membrane lipid remodelling during early stages of mineralization and cell maturation in mineralization-competent cells. Numerous experimental evidences suggested that phospholipases exert their action at various stages of mineralization by affecting intracellular signaling and cell differentiation. The lipid metabolites—such as arachidonic acid, lysophospholipids, and sphingosine-1-phosphate are involved in cell signaling and inflammation reactions. Phospholipases are also important members of the cellular machinery engaged in matrix vesicle (MV) biogenesis and exocytosis. They may favour mineral formation inside MVs, may catalyse MV membrane breakdown necessary for the release of mineral deposits into extracellular matrix (ECM), or participate in hydrolysis of ECM. The biological functions of phospholipases are discussed from the perspective of animal and cellular knockout models, as well as disease implications, development of potent inhibitors and therapeutic interventions.

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Rapid membrane responses to dihydrotestosterone are sex dependent in growth plate chondrocytes

Cited by 16 publications

References 62 publications

Signaling components of the 1α,25(OH)2D3-dependent Pdia3 receptor complex are required for Wnt5a calcium-dependent signaling

Signaling components of the 1α,25(OH)2D3-dependent Pdia3 receptor complex are required for Wnt5a calcium-dependent signaling

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

Phospholipases of Mineralization Competent Cells and Matrix Vesicles: Roles in Physiological and Pathological Mineralizations

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