TY - JOUR
T1 - Integrative Metabolic Pathway Analysis Reveals Novel Therapeutic Targets in Osteoarthritis
AU - Rocha, Beatriz
AU - Cillero-Pastor, Berta
AU - Eijkel, Gert
AU - Calamia, Valentina
AU - Fernandez-Puente, Patricia
AU - Paine, Martin R. L.
AU - Ruiz-Romero, Cristina
AU - Heeren, Ron M. A.
AU - Blanco, Francisco J.
N1 - Funding Information:
* This work has been funded by Fondo Investigación Sanitaria-Spain (grant numbers PI14/01707, PI16/02124, PI17/00404, DTS17/ 00200, CIBER-CB06/01/0040 and RETIC-RIER-RD12/0009/0018), a part of the National Plan for Scientific Program Development and Technological Innovation 2013–2016, funded by the ISCIII-General Subdirection of Assessment and Promotion of Research - European Regional Development Fund (FEDER) “A way of making Europe.” The Proteomics Unit of GIR belongs to ProteoRed, PRB2-ISCIII (grant number PT17/0019/0014). B.R. is supported by Xunta de Galicia (IN606B-2016/004). The research was partially performed within the M4I research program, financially supported by the Dutch Province of Limburg as part of the “LINK” program. The authors declare that they have no conflicts of interest with the contents of this article. □S This article contains supplemental material. ** To whom correspondence may be addressed: INIBIC-Complejo Hospitalario Universitario A Coruña, C/As Xubias, 84; 15006 A Coruña, Spain. Tel.: 34-981-176399; Fax: 34-981-176398; E-mail: fblagar@sergas.es. ‡‡ To whom correspondence may be addressed. E-mail: valentina.calamia@sergas.es.
Funding Information:
This work has been funded by Fondo Investigaci?n Sanitaria- Spain (grant numbers PI14/01707, PI16/02124, PI17/00404, DTS17/ 00200, CIBER-CB06/01/0040 and RETIC-RIER-RD12/0009/0018), a part of the National Plan for Scientific Program Development and Technological Innovation 2013-2016, funded by the ISCIII-General Subdirection of Assessment and Promotion of Research - European Regional Development Fund (FEDER) "A way of making Europe." The Proteomics Unit of GIR belongs to ProteoRed, PRB2- ISCIII (grant number PT17/0019/0014). B.R. is supported by Xunta de Galicia (IN606B-2016/004). The research was partially performed within the M4I research program, financially supported by the Dutch Province of Limburg as part of the "LINK" program. The authors declare that they have no conflicts of interest with the contents of this article.*%blankline%*
Publisher Copyright:
© 2020 Rocha et al.
PY - 2020/4
Y1 - 2020/4
N2 - In osteoarthritis (OA), impairment of cartilage regeneration can be related to a defective chondrogenic differentiation of mesenchymal stromal cells (MSCs). Therefore, understanding the proteomic- and metabolomic-associated molecular events during the chondrogenesis of MSCs could provide alternative targets for therapeutic intervention. Here, a SILAC-based proteomic analysis identified 43 proteins related with metabolic pathways whose abundance was significantly altered during the chondrogenesis of OA human bone marrow MSCs (hBMSCs). Then, the level and distribution of metabolites was analyzed in these cells and healthy controls by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), leading to the recognition of characteristic metabolomic profiles at the early stages of differentiation. Finally, integrative pathway analysis showed that UDP-glucuronic acid synthesis and amino sugar metabolism were downregulated in OA hBMSCs during chondrogenesis compared with healthy cells. Alterations in these metabolic pathways may disturb the production of hyaluronic acid (HA) and other relevant cartilage extracellular matrix (ECM) components. This work provides a novel integrative insight into the molecular alterations of osteoarthritic MSCs and potential therapeutic targets for OA drug development through the enhancement of chondrogenesis.
AB - In osteoarthritis (OA), impairment of cartilage regeneration can be related to a defective chondrogenic differentiation of mesenchymal stromal cells (MSCs). Therefore, understanding the proteomic- and metabolomic-associated molecular events during the chondrogenesis of MSCs could provide alternative targets for therapeutic intervention. Here, a SILAC-based proteomic analysis identified 43 proteins related with metabolic pathways whose abundance was significantly altered during the chondrogenesis of OA human bone marrow MSCs (hBMSCs). Then, the level and distribution of metabolites was analyzed in these cells and healthy controls by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), leading to the recognition of characteristic metabolomic profiles at the early stages of differentiation. Finally, integrative pathway analysis showed that UDP-glucuronic acid synthesis and amino sugar metabolism were downregulated in OA hBMSCs during chondrogenesis compared with healthy cells. Alterations in these metabolic pathways may disturb the production of hyaluronic acid (HA) and other relevant cartilage extracellular matrix (ECM) components. This work provides a novel integrative insight into the molecular alterations of osteoarthritic MSCs and potential therapeutic targets for OA drug development through the enhancement of chondrogenesis.
KW - MESENCHYMAL STEM-CELLS
KW - UDP-GLUCOSE DEHYDROGENASE
KW - SYNOVIAL-FLUID INCREASE
KW - CHONDROGENIC DIFFERENTIATION
KW - MASS-SPECTROMETRY
KW - BONE-MARROW
KW - OSTEOGENIC DIFFERENTIATION
KW - QUANTITATIVE PROTEOMICS
KW - N-ACETYLGLUCOSAMINE
KW - PROLIFERATION
U2 - 10.1074/mcp.RA119.001821
DO - 10.1074/mcp.RA119.001821
M3 - Article
C2 - 31980557
SN - 1535-9476
VL - 19
SP - 574
EP - 588
JO - Molecular & Cellular Proteomics
JF - Molecular & Cellular Proteomics
IS - 4
ER -