Expression of transforming growth factor-  (TGF ) and the TGF  signalling molecule SMAD-2P in spontaneous and instability-induced osteoarthritis: role in cartilage degradation, chondrogenesis and osteophyte formation

Davidson, E.N. Blaney; Vitters, E.L.; Kraan, P.M. van der; Berg, Wim B. van den

doi:10.1136/ard.2005.045971

Cited by 218 publications

(200 citation statements)

References 30 publications

(21 reference statements)

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“…During OA, increasing levels of beta-catenin have also been suggested to, in turn, promote osteophyte formation by upregulating levels of Bmp-2 in mice and human samples [38][39][40] . Bmp-2 is a member of the Transforming Growth Factor super family of signaling proteins, which also contains growth differentiation factors (Gdfs), TGF-betas.…”

Section: Developmental Signaling Pathways In the Pathophysiology Of Oamentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

293

340

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Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here I examined human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, I found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, Ishow in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runtrelated transcription factor-2 (Runx2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (Adamts5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.iii ACKNOWLEDGEMENTS

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Section: Developmental Signaling Pathways In the Pathophysiology Of Oamentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

293

340

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“…For example, reduced TGF-␤1 signaling and absence of TGF-␤1 responsiveness have been associated with spontaneous and surgical models of OA. 56,57 Moreover, the total inhibition of TGF-␤1/Smad signaling by genetic means, such as by the depletion of Smad3 or by overexpressing a dominant-negative TGF-␤ type II receptor, resulted in the overt promotion of terminal chondrocyte differentiation and an OA-like phenotype. 58,59 These data suggest that TGF-␤1/Smad signals maintain articular cartilage tissue by inhibiting chondrocyte terminal differentiation.…”

Section: Discussionmentioning

confidence: 99%

Biglycan and Fibromodulin Have Essential Roles in Regulating Chondrogenesis and Extracellular Matrix Turnover in Temporomandibular Joint Osteoarthritis

Embree

Kilts

Ono

et al. 2010

The American Journal of Pathology

102

110

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The temporomandibular joint is critical for jaw movements and allows for mastication, digestion of food, and speech. Temporomandibular joint osteoarthritis is a degenerative disease that is marked by permanent cartilage destruction and loss of extracellular matrix (ECM). To understand how the ECM regulates mandibular condylar chondrocyte (MCC) differentiation and function, we used a genetic mouse model of temporomandibular joint osteoarthritis that is deficient in two ECM proteins, biglycan and fibromodulin (Bgn Fmod؊/؊ ). Given the unavailability of cell lines, we first isolated primary MCCs and found that they were phenotypically unique from hyaline articular chondrocytes isolated from the knee joint. Using Bgn Fmod؊/؊ MCCs, we discovered the early basis for temporomandibular joint osteoarthritis arises from abnormal and accelerated chondrogenesis. Transforming growth factor (TGF)-␤1 is a growth factor that is critical for chondrogenesis and binds to both biglycan and fibromodulin. Our studies revealed the sequestration of TGF-␤1 was decreased within the ECM of Bgn ؊/0 Fmod ؊/؊ MCCs, leading to overactive TGF-␤1 signal transduction. Using an explant culture system, we found that overactive TGF-␤1 signals induced chondrogenesis and ECM turnover in this model. We demonstrated for the first time a comprehensive study revealing the importance of the ECM in maintaining the mandibular condylar cartilage integrity and identified biglycan and fibromodulin as novel key players in regulating chondrogenesis and ECM turnover during temoporomandibular joint osteoarthritis pathology.

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“…Proinflammatory cytokines (TNF-a, IL-1) and matrix metalloproteinases (MMPs) play central roles in OA (Lories and Luyten 2005;Wojdasiewicz et al 2014). Elevated BMP-2 expression was found in articular chondrocytes of OA mouse models (Blaney Davidson et al 2006). In cartilage, BMP-2 has both anabolic and catabolic effects by stimulating expression of ECM proteins, such as collagen type II, and matrix degrading enzymes, such as MMPs (Blaney Davidson et al 2007; van der Kraan et al 2010).…”

Section: Dysregulation Of Tgf-b or Bmp Signaling In Catabolic Bone DImentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Expression of transforming growth factor- (TGF ) and the TGF signalling molecule SMAD-2P in spontaneous and instability-induced osteoarthritis: role in cartilage degradation, chondrogenesis and osteophyte formation

Cited by 218 publications

References 30 publications

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Biglycan and Fibromodulin Have Essential Roles in Regulating Chondrogenesis and Extracellular Matrix Turnover in Temporomandibular Joint Osteoarthritis

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

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