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Peptidomimetic inhibitor of L-plastin reduces osteoclastic bone resorption in aging female mice

Bone Research 2021年第2期9卷 213-222页

作者： hanan aljohani Joseph P.Stains Sunipa Majumdar Deepa Srinivasan Linda Senbanjo Meenakshi A.Chellaiah Department of Oncology and Diagnostic Sciences School of DentistryUniversity of MarylandBaltimoreMDUSA Department of Oral Medicine and Diagnostics Sciences King Saud UniversitySchool of DentistryRiyadhKingdom of Saudi Arabia Department of Orthopedics University of Maryland School of MedicineBaltimoreMDUSA

L-plastin(LPL)was identified as a potential regulator of the actin-bundling process involved in forming nascent sealing zones(NSZs),which are precursor zones for mature sealing ***-fused cell-penetrating small molecular weight LPL peptide(TATMARGSVSDEE,denoted as an inhibitory LPL peptide)attenuated the formation of NSZs and impaired bone resorption in vitro in ***,the genetic deletion of LPL in mice demonstrated decreased eroded perimeters and increased trabecular bone *** the present study,we hypothesized that targeting LPL with the inhibitory LPL peptide in vivo could reduce osteoclast function and increase bone density in a mice model of low bone *** injected aging C57BL/6 female mice(36 weeks old)subcutaneously with the inhibitory and scrambled peptides of LPL for 14 ***-CT and histomorphometry analyses demonstrated an increase in trabecular bone density of femoral and tibial bones with no change in cortical thickness in mice injected with the inhibitory LPL peptide.A reduction in the serum levels of CTX-1 peptide suggests that the increase in bone density is associated with a decrease in osteoclast *** changes in bone formation rate and mineral apposition rate,and the serum levels of P1NP indicate that the inhibitory LPL peptide does not affect osteoblast *** study shows that the inhibitory LPL peptide can block osteoclast function without impairing the function of *** peptide could be developed as a prospective therapeutic agent to treat osteoporosis.

关键词： function. sealing impaired

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维普期刊数据库

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L-Plastin deficiency produces increased trabecular bone due to attenuation of sealing ring formation and osteoclast dysfunction

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Bone Research 2020年第1期8卷 53-62页

作者： Meenakshi AChellaiah Megan CMoorer Sunipa Majumdar hanan aljohani Sharon CMorley Vanessa Yingling Joseph PStains Department of Oncology and Diagnostic Sciences School of DentistryUniversity of MarylandBaltimoreMDUSA Department of Orthopedics University of Maryland School of MedicineBaltimoreMDUSA Department of Pediatrics Division of Infectious Diseasesand Department of Pathology and ImmunologyWashington University School of MedicineSt.LouisMOUSA Department of Kinesiology California State UniversityEast BayHaywardCAUSA

Bone resorption requires the formation of complex, actin-rich cytoskeletal structures. During the early phase of sealing ring formation by osteoclasts, L-plastin regulates actin-bundling to form the nascent sealing zones(NSZ). Here, we show that L-plastin knockout mice produce osteoclasts that are deficient in the formation of NSZs, are hyporesorptive, and make superficial resorption pits in vitro. Transduction of TAT-fused full-length L-plastin peptide into osteoclasts from L-plastin knockout mice rescued the formation of nascent sealing zones and sealing rings in a time-dependent manner. This response was not observed with mutated full-length L-plastin(Ser-5 and-7 to Ala-5 and-7) peptide. In contrast to the observed defect in the NSZ, L-plastin deficiency did not affect podosome formation or adhesion of osteoclasts in vitro or in vivo. Histomorphometry analyses in 8-and 12-week-old female L-plastin knockout mice demonstrated a decrease in eroded perimeters and an increase in trabecular bone density, without a change in bone formation by osteoblasts. This decrease in eroded perimeters supports that osteoclast function is attenuated in L-plastin knockouts. Micro-CT analyses confirmed a marked increase in trabecular bone mass. In conclusion, female L-plastin knockout mice had increased trabecular bone density due to impaired bone resorption by osteoclasts. L-plastin could be a potential target for therapeutic interventions to treat trabecular bone loss.

关键词： sealing impaired fused

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Identification of sequence-specific interactions of the CD44-intracellular domain with RUNX2 in the transcription of matrix metalloprotease-9 in human prostate cancer cells

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Cancer Drug Resistance 2020年第3期3卷 586-602页

作者： Linda T.Senbanjo hanan aljohani Mohammed AlQranei Sunipa Majumdar Tao Ma Meenakshi A.Chellaiah Department of Oncology and Diagnostic Sciences University of Maryland School of DentistryBaltimoreMD 21201USA.

Aim:The Cluster of differentiation 44(CD44)transmembrane protein is cleaved byγ-secretase,the inhibition of which blocks CD44 *** study aimed to determine the biological consequence of CD44 cleavage and its potential interaction with Runt-related transcription factor(RUNX2)in a sequence-specific manner in PC3 prostate cancer ***:Using full-length and C-terminal deletion constructs of CD44-ICD(D1-D5)expressed as stable green fluorescent protein-fusion proteins in PC3 cells,we located possible RUNX2-binding ***:Chromatin immunoprecipitation assays demonstrated that the C-terminal amino acid residues between amino acids 671 and 706 in D1 to D3 constructs were indispensable for sequence-specific binding of *** binding was minimal for sequences in the D4 and D5 ***,an increase in matrix metalloprotease-9(MMP-9)expression was observed at the mRNA and protein levels in PC3 cells stably expressing D1–D3 ***:These results provide biochemical evidence for the possible sequence-specific CD44-ICD/RUNX2 interaction and its functional relationship to MMP-9 transcription in the promoter region.

关键词： Prostate cancer metastasis CD44 RUNX2 CD44-ICD MMP-9 tumorigenesis

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