Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-β signaling

Zhao, Weiwei; Wang, Ting; Luo, Qiang; Chen, Yan; Leung, Victor; Wen, Chunyi; Shah, Mohammed F.; Pan, Haobo; Chiu, K. Y.; Cao, Xu; Lu, William W.

doi:10.1002/jor.23079

Cited by 70 publications

(66 citation statements)

References 36 publications

(35 reference statements)

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“…In contrast, the chemical inducers may show inhibitory effects instead of stimulation. For example, synovial fibrosis, osteophyte formation, cartilage degeneration or bone remodeling has been previously reported for altered signaling in TGF-β concentration 36 . Furthermore, it has been reported that degeneration of cartilage in osteoarthritis cases can be reduced by inhibition of TGF-β signaling in subchondral bone 37 .…”

Section: Discussionmentioning

confidence: 97%

Cell-Imprinted Substrates Modulate Differentiation, Redifferentiation, and Transdifferentiation

Bonakdar

Mahmoudi

Montazeri

et al. 2016

ACS Appl. Mater. Interfaces

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Differentiation of stem cells into mature cells through the use of physical approaches is of great interest. Here, we prepared smart nanoenvironments by cell-imprinted substrates based on chondrocytes, tenocytes, and semifibroblasts as templates and demonstrated their potential for differentiation, redifferentiation, and transdifferentiation. Analysis of shape and upregulation/downregulation of specific genes of stem cells, which were seeded on these cell-imprinted substrates, confirmed that imprinted substrates have the capability to induce specific shapes and molecular characteristics of the cell types that were used as templates for cell-imprinting. Interestingly, immunofluorescent staining of a specific protein in chondrocytes (i.e., collagen type II) confirmed that adipose-derived stem cells, semifibroblasts, and tenocytes can acquire the chondrocyte phenotype after a 14 day culture on chondrocyte-imprinted substrates. In summary, we propose that common polystyrene tissue culture plates can be replaced by this imprinting technique as an effective and promising way to regulate any cell phenotype in vitro with significant potential applications in regenerative medicine and cell-based therapies.

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Section: Discussionmentioning

confidence: 97%

Cell-Imprinted Substrates Modulate Differentiation, Redifferentiation, and Transdifferentiation

Bonakdar

Mahmoudi

Montazeri

et al. 2016

ACS Appl. Mater. Interfaces

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“…Secondly, TGFβ signaling through the smad2/3 pathway is its canonical pathway. Therefore, in present study, the expression of TGFβ1 and pSmad2/3 was detected by immunohistochemistry with reference to previous research findings (8,9,12). Although statistical correlation and in vitro analysis were performed to determine the effect of activating osteocyte TGFβ signaling pathway on osteogenesis and osteoclast differentiation, a direct relationship between osteocyte TGFβ signal and the development of OA remains to be elucidated.…”

Section: Ratio Of P-smad2/3-positive Osteocytes Bone Turnover -------mentioning

confidence: 91%

“…Transforming growth factor β (TGFβ), canonically binds to its cell surface receptor and then directly phosphorylates Smad2/3 to translocate the signaling molecule into the nucleus and interact with other transcriptional factors, playing an important role in the development of OA (8)(9)(10)(11)(12)(13). However, the effect of TGFβ on OA varies depending on the sites it acts on.…”

Section: Introductionmentioning

confidence: 99%

“…conversely, in adult knee joints, chondrocyte TGFβ1 could induce extracellular matrix-degrading enzymes (17). Yet, in the subchondral bone of OA, a large amount of TGFβ was activated in the extracellular matrix (8). Moreover, it has been suggested that osteoblastic TGFβ signaling in subchondral bone might play an important role in the pathogenesis of OA by altering mesenchymal stem cell (MSc) osteogenic activity (9).…”

Section: Introductionmentioning

confidence: 99%

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Osteocyte TGFβ1‑Smad2/3 is positively associated with bone turnover parameters in subchondral bone of advanced osteoarthritis

et al. 2020

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Subchondral sclerosis is considered the main characteristic of advanced osteoarthritis, in which bone remodeling mediated by transforming growth factor β (TGFβ) signaling plays an indispensable role in the metabolism. Osteocytes have been identified as pivotal regulators of bone metabolism, due to their mechanosensing and endocrine function. Therefore, the aim of the present study was to investigate the association between osteocyte TGFβ signal and subchondral sclerosis. Knee tibia plateau samples were collected from osteoarthritic patients and divided into three groups: The full cartilage, partial cartilage and full defect groups. Next, changes in osteocyte TGFβ signaling and subchondral bone structure underlying various types of cartilage erosion were detected. Bone mineral density (BMd) assay, histology [hematoxylin and eosin, Safranin-O/Fast green, and tartrate resistant acid phosphatase (TRAP) staining], and reverse transcription-quantitative PcR mainly detected structural alterations, osteogenic and osteoclastic activity in the cartilage and subchondral bone. The activation of the TGFβ signaling pathway in the subchondral bone was detected by immunohistochemistry and western blotting. The association between osteocyte TGFβ and the regulation of bone metabolism was analyzed by correlation analysis, and further proven in vitro. It was confirmed that the BMd of the subchondral bone increased and underwent sclerosis in the partial cartilage and full defect groups. Additional observation included the thinning of the area of calcified cartilage, in which a bone island formed locally, with subchondral bone plate thickening and increased trabecular bone volume. TRAP staining suggested an increase in bone resorption in subchondral underlying areas of the partial cartilage and full defect groups. Immunohistochemistry results confirmed the activation of osteocyte TGFβ in subchondral underlying areas with severe cartilage erosion. Moreover, osteocyte phosphorylated-Smad2/3 was positively correlated with subchondral BMd, alkaline phosphatase and osteopontin mRNA expression, but it was negatively correlated with TRAP + cells. Furthermore, it was confirmed in vitro that osteocyte TGFβ signaling could regulate the osteogenic and osteoclastic activity of the mesenchymal stem cells. This study illustrated that osteocyte TGFβ signaling is positively associated with the remodeling of subchondral bone in advanced osteoarthritis and provides a preliminary theoretical basis for further investigations of the role and mechanism of osteocyte TGFβ in subchondral of osteoarthritis.

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“…While required for early chondrogenesis, signaling through ALK 1, and subsequent phosphorylation of SMAD 1/5/8 has been implicated in the terminal differentiation of MSCs . Furthermore, the impact of TGF‐β on chondrocyte differentiation may be altered in response to aging and increasing evidence implicates altered TGF‐β signaling in the progression of OA . Dynamic mechanical compression at 1 Hz with 3 MPa stress has been previously reported to activate the ALK 5/SMAD 2/3 signaling pathway in bovine articular cartilage explants, highlighting a protective effect of mechanical stimulation on articular cartilage .…”

Section: Role Of Mechanical Stimulation and Cartilage Developmentmentioning

confidence: 99%

Mechanical stimulation of mesenchymal stem cells: Implications for cartilage tissue engineering

Fahy

Alini

Stoddart

2017

Journal Orthopaedic Research

180

138

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Articular cartilage is a load-bearing tissue playing a crucial mechanical role in diarthrodial joints, facilitating joint articulation, and minimizing wear. The significance of biomechanical stimuli in the development of cartilage and maintenance of chondrocyte phenotype in adult tissues has been well documented. Furthermore, dysregulated loading is associated with cartilage pathology highlighting the importance of mechanical cues in cartilage homeostasis. The repair of damaged articular cartilage resulting from trauma or degenerative joint disease poses a major challenge due to a low intrinsic capacity of cartilage for self-renewal, attributable to its avascular nature. Bone marrow-derived mesenchymal stem cells (MSCs) are considered a promising cell type for cartilage replacement strategies due to their chondrogenic differentiation potential. Chondrogenesis of MSCs is influenced not only by biological factors but also by the environment itself, and various efforts to date have focused on harnessing biomechanics to enhance chondrogenic differentiation of MSCs. Furthermore, recapitulating mechanical cues associated with cartilage development and homeostasis in vivo, may facilitate the development of a cellular phenotype resembling native articular cartilage. The goal of this review is to summarize current literature examining the effect of mechanical cues on cartilage homeostasis, disease, and MSC chondrogenesis. The role of biological factors produced by MSCs in response to mechanical loading will also be examined. An in-depth understanding of the impact of mechanical stimulation on the chondrogenic differentiation of MSCs in terms of endogenous bioactive factor production and signaling pathways involved, may identify therapeutic targets and facilitate the development of more robust strategies for cartilage replacement using MSCs. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:52-63, 2018.

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Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-β signaling

Cited by 70 publications

References 36 publications

Cell-Imprinted Substrates Modulate Differentiation, Redifferentiation, and Transdifferentiation

Cell-Imprinted Substrates Modulate Differentiation, Redifferentiation, and Transdifferentiation

Osteocyte TGFβ1‑Smad2/3 is positively associated with bone turnover parameters in subchondral bone of advanced osteoarthritis

Mechanical stimulation of mesenchymal stem cells: Implications for cartilage tissue engineering

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