PMID- 37088847
OWN - NLM
STAT- MEDLINE
DCOM- 20230425
LR  - 20230425
IS  - 1423-0127 (Electronic)
IS  - 1021-7770 (Print)
IS  - 1021-7770 (Linking)
VI  - 30
IP  - 1
DP  - 2023 Apr 23
TI  - Downregulation of the RNA-binding protein PUM2 facilitates MSC-driven bone 
      regeneration and prevents OVX-induced bone loss.
PG  - 26
LID - 10.1186/s12929-023-00920-8 [doi]
LID - 26
AB  - BACKGROUND: Although mRNA dysregulation can induce changes in mesenchymal stem 
      cell (MSC) homeostasis, the mechanisms by which post-transcriptional regulation 
      influences MSC differentiation potential remain understudied. PUMILIO2 (PUM2) 
      represses translation by binding target mRNAs in a sequence-specific manner. 
      METHODS: In vitro osteogenic differentiation assays were conducted using human 
      bone marrow-derived MSCs. Alkaline phosphatase and alizarin red S staining were 
      used to evaluate the osteogenic potential of MSCs. A rat xenograft model 
      featuring a calvarial defect to examine effects of MSC-driven bone regeneration. 
      RNA-immunoprecipitation (RNA-IP) assay was used to determine the interaction 
      between PUM2 protein and Distal-Less Homeobox 5 (DLX5) mRNA. Ovariectomized (OVX) 
      mice were employed to evaluate the effect of gene therapy for postmenopausal 
      osteoporosis. RESULTS: Here, we elucidated the molecular mechanism of PUM2 in MSC 
      osteogenesis and evaluated the applicability of PUM2 knockdown (KD) as a 
      potential cell-based or gene therapy. PUM2 level was downregulated during MSC 
      osteogenic differentiation, and PUM2 KD enhanced MSC osteogenic potential. 
      Following PUM2 KD, MSCs were transplanted onto calvarial defects in 12-week-old 
      rats; after 8 weeks, transplanted MSCs promoted bone regeneration. PUM2 KD 
      upregulated the expression of DLX5 mRNA and protein and the reporter activity of 
      its 3'-untranslated region. RNA-IP revealed direct binding of PUM2 to DLX5 mRNA. 
      We then evaluated the potential of adeno-associated virus serotype 9 
      (AAV9)-siPum2 as a gene therapy for osteoporosis in OVX mice. CONCLUSION: Our 
      findings suggest a novel role for PUM2 in MSC osteogenesis and highlight the 
      potential of PUM2 KD-MSCs in bone regeneration. Additionally, we showed that 
      AAV9-siPum2 is a potential gene therapy for osteoporosis.
CI  - (c) 2023. The Author(s).
FAU - Yoon, Dong Suk
AU  - Yoon DS
AD  - Department of Biomedical Science, Hwasung Medi-Science University, Hwaseong-Si 
      18274, Gyeonggi-Do, South Korea.
FAU - Choi, Yoorim
AU  - Choi Y
AD  - Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, 
      03722, South Korea.
FAU - Lee, Kyoung-Mi
AU  - Lee KM
AD  - Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, 
      03722, South Korea.
FAU - Ko, Eun Ae
AU  - Ko EA
AD  - Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, 
      03722, South Korea.
FAU - Kim, Eun-Ji
AU  - Kim EJ
AD  - Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, 
      03722, South Korea.
AD  - Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of 
      Medicine, Seoul, 03722, South Korea.
FAU - Park, Kwang Hwan
AU  - Park KH
AD  - Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, 
      03722, South Korea.
FAU - Lee, Jin Woo
AU  - Lee JW
AD  - Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, 
      03722, South Korea. ljwos@yuhs.ac.
AD  - Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of 
      Medicine, Seoul, 03722, South Korea. ljwos@yuhs.ac.
LA  - eng
GR  - NRF-2021R1C1C2093717/National Research Foundation of Korea/
PT  - Journal Article
DEP - 20230423
PL  - England
TA  - J Biomed Sci
JT  - Journal of biomedical science
JID - 9421567
RN  - 63231-63-0 (RNA)
RN  - 0 (RNA, Messenger)
RN  - 0 (PUM2 protein, human)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Pum2 protein, mouse)
SB  - IM
MH  - Humans
MH  - Rats
MH  - Mice
MH  - Animals
MH  - Osteogenesis/genetics
MH  - Down-Regulation
MH  - Cell Differentiation
MH  - Bone Regeneration/genetics
MH  - *Mesenchymal Stem Cells
MH  - *Osteoporosis
MH  - RNA
MH  - RNA, Messenger/metabolism
MH  - Cells, Cultured
MH  - RNA-Binding Proteins/genetics/metabolism
PMC - PMC10122812
OTO - NOTNLM
OT  - Bone regeneration
OT  - Gene therapy
OT  - Mesenchymal stem cells
OT  - Osteoporosis
OT  - PUMILIO2
COIS- The authors declare no competing interests.
EDAT- 2023/04/24 00:41
MHDA- 2023/04/25 10:20
PMCR- 2023/04/23
CRDT- 2023/04/23 23:15
PHST- 2022/07/28 00:00 [received]
PHST- 2023/04/14 00:00 [accepted]
PHST- 2023/04/25 10:20 [medline]
PHST- 2023/04/24 00:41 [pubmed]
PHST- 2023/04/23 23:15 [entrez]
PHST- 2023/04/23 00:00 [pmc-release]
AID - 10.1186/s12929-023-00920-8 [pii]
AID - 920 [pii]
AID - 10.1186/s12929-023-00920-8 [doi]
PST - epublish
SO  - J Biomed Sci. 2023 Apr 23;30(1):26. doi: 10.1186/s12929-023-00920-8.