Parathyroid hormone signaling through low-density lipoprotein-related protein 6

Wan, Mei; Yang, Chaozhe; Jun, Li; Wu, Xiangwei; Yuan, Hongling; Ma, Hao; He, Xi; Nie, Shuyi; Chang, Chenbei; Cao, Xu

doi:10.1101/gad.1702708

Cited by 209 publications

(224 citation statements)

References 61 publications

(67 reference statements)

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“…Alternatively, data from another in vitro study showed evidence for PTH-induced association of the PTH receptor with LRP6, leading to activation of LRP6 and canonical Wnt signaling. (71) This report raises the possibility that PTH might act directly on the Wnt signaling pathway through LRP6, irrespective of any decreases in sclerostin expression. Interestingly, two studies demonstrated a normal anabolic response to intermittent PTH in LRP5-deficient mice (LRP5 knockouts), indicating that LRP5 is not needed for intermittent PTHs stimulatory effects on bone formation.…”

Section: Osteocytes Mechanical Loading and Interface With The Pth Pmentioning

confidence: 73%

Sclerostin: A gem from the genome leads to bone-building antibodies

Pászty

Turner

Robinson

2010

Journal of Bone and Mineral Research

113

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Discovery of SclerostinG enomics technologies and DNA sequencing have had a transformative impact on biological research, giving us unprecedented access to the genomes of numerous organisms and ushering in such new fields as systems biology (1) and, more recently, synthetic biology. (2,3) In the 1990s, the advent of highthroughput sequencing spurred application of this powerful new technology to the challenging endeavor of trying to understand the genetic basis of various inherited human diseases. One such disease was sclerosteosis, a very rare, recessively inherited highbone-mass disorder that was thought to be caused primarily by excessive osteoblast-mediated bone formation rather than by defective osteoclast-mediated bone resorption. (4,5) Within the realm of inherited high-bone-mass disorders, (6) it was the hope for a discovery in the area of osteoblast biology that made sclerosteosis particularly interesting.Indeed, the identification of new bone-building pathways that might yield novel anabolic agents had been a long-standing goal in bone biology, with hopes for therapeutic application in fracture healing, orthopedic procedures, and low-bone-mass conditions such as osteoporosis. Against this backdrop came the exciting news, independently from Mary Brunkow's group at Celltech R&D, Inc., (7,8) and from Wim Van Hul's group at the University of Antwerp, (9) that sclerosteosis was caused by mutations in a single gene (SOST) encoding a novel secreted protein. Because these were inactivating mutations, it was clear that this protein, aptly given the name sclerostin, functioned either directly or indirectly as an inhibitor of bone formation. During this same general time period, large-scale cDNA/ expressed sequence tag (EST) (10)(11)(12) and genomic DNA sequencing efforts were being made in academia and industry to rapidly identify new human genes. A novel secreted protein of unknown function, which turned out to be sclerostin, was discovered by computational mining of large DNA sequence databases using either homology-based programs (eg, BLAST) (13,14) or a special CxGxC-class cystine-knot search pattern (C Paszty, unpublished) (15) designed to identify new families of cystine-knot proteins. (16,17) Thus sclerostin emerged during an exciting era of gene discovery that was fueled, in part, by the development of important genomics technologies and the advent of high-throughput DNA sequencing.Similar to sclerostin inactivation in humans, mice with a targeted deletion of the sclerostin gene (SOST knockout mice) were found to have high bone mass, demonstrating evolutionary conservation of sclerostin's function as a negative regulator of bone formation. (18) Analysis of bones from these mice revealed that bone formation was markedly increased on each of the key skeletal surfaces where new bone is normally formed (surface of trabecular bone and internal and external surfaces of cortical bone). Consistent with the increases in bone formation and bone mass, robust increases in bone strength also were found in these anima...

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Section: Osteocytes Mechanical Loading and Interface With The Pth Pmentioning

confidence: 73%

Sclerostin: A gem from the genome leads to bone-building antibodies

Pászty

Turner

Robinson

2010

Journal of Bone and Mineral Research

113

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“…Intermittent but not continuous PTH has also been shown to induce b-catenin signaling by directly binding to LRP6/frizzled complex. (75) It is assumed that hyperparathyroidism is analogous to continuous PTH administration such that these findings using intermittent PTH would not be relevant in the setting of CKD. (75) In support of this, transgenic mice expressing constitutively active PTH receptors have a bone phenotype similar to osteitis fibrosa.…”

Section: Discussionmentioning

confidence: 99%

“…(75) It is assumed that hyperparathyroidism is analogous to continuous PTH administration such that these findings using intermittent PTH would not be relevant in the setting of CKD. (75) In support of this, transgenic mice expressing constitutively active PTH receptors have a bone phenotype similar to osteitis fibrosa. (74) However, it is also possible that elevations in sclerostin may contribute to repression of PTH signaling in CKD bones because PTH responses are blunted in transgenic mice overexpressing sclerostin.…”

Section: Discussionmentioning

confidence: 99%

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

232

219

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Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy. © 2012 American Society for Bone and Mineral Research.

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“…9,43 It is worth mentioning that the transcriptional activity of b-catenin may also occur independent of the activation of Wnt and Fz. Activation of G protein-coupled receptors such as prostanoid (EP2, EP4), 44 lysophosphatidic acid (LPA2, LPA3), 18,45 gonadotrophin releasing hormone 46 and parathyroid 47 can also turn on b-cateninmediated gene transcriptional programs. In a recent study, it has been shown that the free G a and G bg subunits released from an activated G protein act co-operatively to inhibit b-catenin degradation and subsequently activate b-catenin-mediated transcriptional program.…”

Section: Canonical Wnt Pathwaymentioning

confidence: 99%

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

Balakumar

Jagadeesh

2011

Hypertens Res

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The renin-angiotensin system and Wnt/frizzled receptor signaling pathways are important in the development of essential organs, and their aberrant activation results in cardiovascular and renal pathologies. The (pro)renin receptor ((P)RR)-bound (pro)renin is enzymatically active generating angiotensin-II and activating mitogen-activated protein kinases, leading to cell proliferation and to upregulation of profibrotic genes expression, resulting in end-organ damage. The (P)RR does more than bind to (pro)renin, because it is functionally linked to the vacuolar-H + -ATPase (v-H + -ATPase) that regulates pH of cellular and intracellular vesicles, and to Wnt signaling. This signaling pathway is essential for cell survival, embryonic development and has had a role in various disease states as evidenced by mutation or genetic ablation of the (P)RR gene. This suggests two types of functions of (P)RRs, first one as a receptor for (pro)renin and second one as an accessory subunit of the v-H + -ATPase and a cofactor of the Wnt/Fz receptor complex. This review will discuss both of these functions of (P)RRs thereby giving new perspectives as to the roles of (P)RRs in cardiovascular and renal pathologies.

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Parathyroid hormone signaling through low-density lipoprotein-related protein 6

Cited by 209 publications

References 61 publications

Sclerostin: A gem from the genome leads to bone-building antibodies

Sclerostin: A gem from the genome leads to bone-building antibodies

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

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