Downregulation of Heat Shock Protein 70 Impairs Osteogenic and Chondrogenic Differentiation in Human Mesenchymal Stem Cells

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Abstract

Human mesenchymal stem cells (hMSCs) show promise for bone and cartilage regeneration. Our previous studies demonstrated that hMSCs with periodic mild heating had enhanced osteogenic and chondrogenic differentiation with significantly upregulated heat shock protein 70 (HSP70). However, the role of HSP70 in adult tissue regeneration is not well studied. Here, we revealed an essential regulatory mechanism of HSP70 in osteogenesis and chondrogenesis using adult hMSCs stably transfected with specific shRNAs to knockdown HSP70. Periodic heating at 39 °C was applied to hMSCs for up to 26 days. HSP70 knockdown resulted in significant reductions of alkaline phosphatase activity, calcium deposition, and gene expression of Runx2 and Osterix during osteogenesis. In addition, knockdown of HSP70 led to significant decreases of collagens II and X during chondrogenesis. Thus, downregulation of HSP70 impaired hMSC osteogenic and chondrogenic differentiation as well as the enhancement of these processes by thermal treatment. Taken together, these findings suggest a putative mechanism of thermal-enhanced bone and cartilage formation and underscore the importance of HSP70 in adult bone and cartilage differentiation.

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Structure and function of aggrecan.

Chris Kiani, Liwen Chen, Yao Wu … (2002)

Aggrecan is the major proteoglycan in the articular cartilage. This molecule is important in the proper functioning of articular cartilage because it provides a hydrated gel structure (via its interaction with hyaluronan and link protein) that endows the cartilage with load-bearing properties. It is also crucial in chondroskeletal morphogenesis during development. Aggrecan is a multimodular molecule expressed by chondrocytes. Its core protein is composed of three globular domains (G1, G2, and G3) and a large extended region (CS) between G2 and G3 for glycosaminoglycan chain attachment. G1 comprises the amino terminus of the core protein. This domain has the same structural motif as link protein. Functionally, the G1 domain interacts with hyaluronan acid and link protein, forming stable ternary complexes in the extracellular matrix. G2 is homologous to the tandem repeats of G1 and of link protein and is involved in product processing. G3 makes up the carboxyl terminus of the core protein. It enhances glycosaminoglycan modification and product secretion. Aggrecan plays an important role in mediating chondrocyte-chondrocyte and chondrocyte-matrix interactions through its ability to bind hyaluronan.

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Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis.

Marissa V Powers, Paul A Clarke, Paul Workman (2008)

Heat-shock protein 70 (HSP70) isoforms contribute to tumorigenesis through their well-documented antiapoptotic activity and via their role as cochaperones for the HSP90 molecular chaperone. HSP70 expression is induced following treatment with HSP90 inhibitors, which may attenuate the cell death effects of this class of inhibitor. Here we show that silencing either heat-shock cognate 70 (HSC70) or HSP72 expression in human cancer cell lines has no effect on HSP90 activity or cell proliferation. However, simultaneously reducing the expression of both of these isoforms induces proteasome-dependent degradation of HSP90 client proteins, G1 cell-cycle arrest, and extensive tumor-specific apoptosis. Importantly, simultaneous silencing of HSP70 isoforms in nontumorigenic cell lines does not result in comparable growth arrest or induction of apoptosis, indicating a potential therapeutic window.

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Positive effects of moderate exercise on glycosaminoglycan content in knee cartilage: a four-month, randomized, controlled trial in patients at risk of osteoarthritis.

Leif Dahlberg, Leif Dahlberg (2005)

To evaluate the effects of moderate exercise on glycosaminoglycan (GAG) content in knee cartilage in subjects at high risk of knee osteoarthritis (OA). Forty-five subjects (16 women, mean age 46 years, mean body mass index 26.6 kg/m(2)) who underwent partial medial meniscus resection 3-5 years previously were randomized to undergo a regimen of supervised exercise 3 times weekly for 4 months or to a nonintervention control group. Cartilage GAG content, an important aspect of the biomechanical properties of cartilage, was estimated by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC), with results expressed as the change in the T1 relaxation time in the presence of Gd-DTPA (T1[Gd]). Thirty of 45 patients were examined by dGEMRIC at baseline and followup. The exercise group (n = 16) showed an improvement in the T1(Gd) compared with the control group (n = 14) (15 msec versus -15 msec; P = 0.036). To study the dose response, change in the T1(Gd) was assessed for correlation with self-reported change in physical activity level, and a strong correlation was found in the exercise group (n = 16, r(S) = 0.70, 95% confidence interval [95% CI] 0.31-0.89) and in the pooled group of all subjects (n = 30, r(S) = 0.74, 95% CI 0.52-0.87). This in vivo cartilage monitoring study in patients at risk of knee OA who begin exercising indicates that adult human articular cartilage has a potential to adapt to loading change. Moderate exercise may be a good treatment not only to improve joint symptoms and function, but also to improve the knee cartilage GAG content in patients at high risk of developing OA.

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Author and article information

Contributors

Sihong Wang: shwang@ccny.cuny.edu

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 11 January 2018

Publication date PMC-release: 11 January 2018

Publication date Collection: 2018

Volume: 8

Electronic Location Identifier: 553

Affiliations

ISNI 0000 0001 2264 7145, GRID grid.254250.4, Department of Biomedical Engineering, , City University of New York-City College, 160 Convent Avenue, ; New York, NY 10031 USA

Article

Publisher ID: 18541

DOI: 10.1038/s41598-017-18541-1

PMC ID: 5765044

PubMed ID: 29323151

SO-VID: 91864b11-a54a-49e9-8482-ff2d5d348c0b

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 10 August 2017

Date accepted : 12 December 2017

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Downregulation of Heat Shock Protein 70 Impairs Osteogenic and Chondrogenic Differentiation in Human Mesenchymal Stem Cells

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Most cited references 41

Structure and function of aggrecan.

Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis.

Positive effects of moderate exercise on glycosaminoglycan content in knee cartilage: a four-month, randomized, controlled trial in patients at risk of osteoarthritis.

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Cited by 13

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