Emerging therapeutic opportunities for skeletal restoration

Kawai, Masanobu; Mödder, Ulrike I.; Khosla, Sundeep; Rosen, Clifford J.

doi:10.1038/nrd3299

Cited by 128 publications

(116 citation statements)

References 177 publications

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“…sFRP3 is an inhibitor of signaling by the wingless-type MMTV integration site family (wnt) pathway. Because wnt signaling potently regulates the balance between bone formation and bone resorption [50], one possibility is that reduced wnt signaling during aseptic loosening further skews that balance against bone formation. Consistent with that possibility, antibodies that neutralize sclerostin, an inhibitor of wnt signaling, block the negative effect of polyethylene particles on implant fixation in rats by increasing bone formation and decreasing bone resorption [60].…”

Section: Where Are We Now?mentioning

confidence: 99%

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

Greenfield

2014

Clin Orthop Relat Res

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Background Overwhelming evidence supports the concept that wear particles are the primary initiator of aseptic loosening of orthopaedic implants. It is likely, however, that other factors modulate the biologic response to wear particles. This review focuses on three potential other factors: genetic susceptibility, Toll-like receptors (TLRs), and bacterial pathogen-associated molecular patterns (PAMPs). Where Are We Now? Considerable evidence is emerging that both genetic susceptibility and TLR activation are important factors that modulate the biologic response to wear particles, but it remains controversial whether bacterial PAMPs also do so. Where Do We Need to Go? Detailed understanding of the roles of these other factors may lead to identification of novel therapeutic targets for patients with aseptic loosening. How Do We Get There? Highest priority should be given to polymorphism replication studies with large numbers of patients and studies to replicate the reported correlation between bacterial biofilms and the severity of aseptic loosening.

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Section: Where Are We Now?mentioning

confidence: 99%

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

Greenfield

2014

Clin Orthop Relat Res

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“…An endocrine function for NHERF1 can be inferred from two sources. First, lesions in the NHERF1 gene contribute to excessive urinary phosphate (P i ) excretion and skeletal defects in humans that are emblematic of abnormalities of the action of parathyroid hormone (PTH) (11)(12)(13). Second, NHERF1…”

Section: Pdzmentioning

confidence: 99%

Ezrin-anchored Protein Kinase A Coordinates Phosphorylation-dependent Disassembly of a NHERF1 Ternary Complex to Regulate Hormone-sensitive Phosphate Transport

Wang

Means

Yang

et al. 2012

Journal of Biological Chemistry

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Background: Some inherited defects in NHERF1 are associated with high phosphate (P i ) excretion and skeletal abnormalities. Results: NHERF1 forms a multiprotein complex with Npt2a and ezrin. Mutants fail to assemble this ternary complex. Conclusion:The NHERF1 ternary complex is required for PTH-sensitive P i transport. Significance: NHERF1 mutations may cause disease processes through structural changes that prevent assembly of multiprotein complexes.

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“…PTH(1-34) (teriparatide) is the only anabolic drug on the US market for treatment of osteoporosis (Kawai et al, 2011). Although intermittent administration of PTH(1-34) promotes bone formation and reduces the incidence of fracture, continuous administration promotes bone resorption and hypercalcemia dx.doi.org/10.1124/jpet.112.199752. s This article has supplemental material available at jpet.aspetjournals.org.…”

Section: Introductionmentioning

confidence: 99%

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Cupp¹,

Nayak²,

Adem³

et al. 2013

J Pharmacol Exp Ther

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Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), acting through the osteoblast PTH1 receptor (PTH1R), play important roles in bone remodeling. Intermittent administration of PTH(1-34) (teriparatide) leads to bone formation, whereas continuous administration paradoxically leads to bone resorption. Activation of PTH1R promotes regulation of multiple signaling pathways, including G s /cAMP/protein kinase A, G q /calcium/protein kinase C, b-arrestin recruitment, and extracellular signal-related kinase (ERK)1/2 phosphorylation, as well as receptor internalization, but their role in promoting anabolic and catabolic actions of PTH(1-34) are unclear. In the present investigation, a collection of PTH(1-34) and PTHrP(1-34) peptide analogs were evaluated in orthogonal human PTH1R (hPTH1R) functional assays capturing G s -and G q -signaling, b-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization to further define the patterns of PTH1R signaling that they stimulate and further establish peptide domains contributing to agonist activity. Results indicate that both Nand C-terminal domains of PTH and PTHrP are critical for activation of signaling pathways. However, modifications of both regions lead to more substantial decreases in agonist potency and efficacy to stimulate G q -signaling, b-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization than to stimulate G s -signaling. The substantial contribution of the peptide C-terminal domain in activation of hPTH1R signaling suggests a role in positioning of the peptide N-terminal region into the receptor J-domain. Several PTH and PTHrP peptides evaluated in this study promote different patterns of biased agonist signaling and may serve as useful tools to further elucidate therapeutically relevant PTH1R signaling in osteoblasts. With a better understanding of therapeutically relevant signaling, novel biased peptides with desired signaling could be designed for safer and more effective treatment of osteoporosis.

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Emerging therapeutic opportunities for skeletal restoration

Cited by 128 publications

References 177 publications

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

Ezrin-anchored Protein Kinase A Coordinates Phosphorylation-dependent Disassembly of a NHERF1 Ternary Complex to Regulate Hormone-sensitive Phosphate Transport

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

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