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Cited by 25Bone Metabolism and DiseasesBone health and osteoporosis researchUbiquitin and proteasome pathways

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The Proteasome Inhibitor Carfilzomib Suppresses Parathyroid Hormone-induced Osteoclastogenesis through a RANKL-mediated Signaling Pathway

Open access
Yang, Yanmei, Blair, Harry C., Shapiro, Irving M., Wang, Bin·2015·Journal of Biological Chemistry
DOI 10.1074/jbc.m115.663963PMC PMC4505437
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Abstract

Parathyroid hormone (PTH) induces osteoclast formation and activity by increasing the ratio of RANKL/OPG in osteoblasts. The proteasome inhibitor carfilzomib (CFZ) has been used as an effective therapy for multiple myeloma via the inhibition of pathologic bone destruction. However, the effect of combination of PTH and CFZ on osteoclastogenesis is unknown. We now report that CFZ inhibits PTH-induced RANKL expression and secretion without affecting PTH inhibition of OPG expression, and it does so by blocking HDAC4 proteasomal degradation in osteoblasts. Furthermore, we used different types of culture systems, including co-culture, indirect co-culture, and transactivation, to assess the effect of CFZ on PTH action to induce osteoclastogenesis. Our results demonstrated that CFZ blocks PTH-induced osteoclast formation and bone resorption by its additional effect to inhibit RANKL-mediated IκB degradation and NF-κB activation in osteoclasts. This study showed for the first time that CFZ targets both osteoblasts and osteoclasts to suppress PTH-induced osteoclast differentiation and bone resorption. These findings warrant further investigation of this novel combination in animal models of osteoporosis and in patients.

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  • Carfilzomib activates NF-κB, which mediates TNF-α-induced tumor initiation and promotion.

    “Carfilzomib (CFZ), the second FDA-approved proteasome inhibitor for MM treatment, activates NF-κB, which mediates TNF-α-induced tumor initiation and promotion [151].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [151]

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Metadata

Authors
Yang, Y., Blair, H. C., Shapiro, I. M., & Wang, B.
Affiliations
  • Center for Translational Medicine (PL)
  • University of Pittsburgh (US)
  • Thomas Jefferson University (US)
Corresponding author
Wang, Bin
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2015-07
Volume
290
Issue
27
Pages
16918-16928
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m115.663963
PMC
PMC4505437
OpenAlex
W285492224
Cited by
25
References
0
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2021: 3 · 2020: 5 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 7 · 2015: 1
FWCI
1.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (AR062705, AR063289)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
carfilzomib, parathyroid hormone, osteoclastogenesis, RANKL, osteoprotegerin, proteasome inhibition, HDAC4, osteoblasts, osteoclasts, bone resorption, NF-κB activation, IκB degradation, osteoporosis
MeSH terms
Animals, Bone Resorption, Cell Differentiation, Cells, Cultured, Humans, Mice, Inbred C57BL, Oligopeptides, Osteoblasts, Osteoclasts, Parathyroid Hormone, Signal Transduction, NF-kappa B, Mice, Osteoprotegerin, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Proteasome Inhibitors

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