Expression of a Truncated, Kinase-Defective TGF-β Type II Receptor in Mouse Skeletal Tissue Promotes Terminal Chondrocyte Differentiation and Osteoarthritis

Serra, Rosa; Johnson, Mahlon D.; Filvaroff, Ellen; LaBorde, James B.; Sheehan, Daniel M.; Derynck, Rik; Moses, Harold L.

doi:10.1083/jcb.139.2.541

Cited by 450 publications

(379 citation statements)

References 69 publications

Supporting

Mentioning

362

Contrasting

Unclassified

Order By: Relevance

“…Many growth factors and cytokines have been shown to influence the pathogenesis of osteoarthritis (14), such as transforming growth factor ␤ (TGF-␤) (16)(17)(18)(19)(20)(21)(22) and bone morphogenetic proteins (BMPs) (23). In addition, genetic predisposition to osteoarthritis has been linked to mutations in genes like COL2A1 (24).…”

Section: Resultsmentioning

confidence: 99%

Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease

Zhang

Lanning

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

112

View full text Add to dashboard Cite

Degenerative joint disease, also known as osteoarthritis, is the most common joint disorder in human beings. The molecular mechanism underlying this disease is not fully understood. Here, we report that disruption of mitogen-inducible gene 6 (Mig-6) in mice by homologous recombination leads to early onset degenerative joint disease, which is revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage, and the development of bony outgrowths or osteophyte formation within joint space. The osteophyte formation appears to be derived from proliferation of mesenchymal progenitor cells followed by differentiation into chondrocytes. Absence of the Rag2 gene does not rescue the joint phenotype, excluding a role for the acquired immune system in the development of this disease. Our results provide insight into the mechanism of osteoarthritis by showing that loss of Mig-6 leads to early onset of this disease, implying that this gene or its pathway is important in normal joint maintenance. Because of the striking similarity of osteoarthritis in humans and mice, the Mig-6 mutant mouse should provide a useful animal model for studying the mechanism of this disease and for testing drugs or therapies for treating osteoarthritis.animal model ͉ mutation ͉ osteoarthritis ͉ bony outgrowth ͉ signaling pathway D egenerative joint disease, or osteoarthritis, affects nearly 12% of the population between ages 25 and 74 in the United States (1) and greatly interferes with quality of life by causing acute and chronic pain and disability (2, 3). The characteristic features of this disease are joint pain, stiffness, joint enlargement and malalignment, damage of articular cartilage, and formation of osteophytes or bony outgrowths at the margin of the synovial and cartilage junctions (2, 3). Currently, therapy is directed toward controlling symptoms, and no disease-modifying or chondroprotective treatment is available (2, 3). In addition, the costs for pain relief medication are astronomical. Although several genetic and biomechanical factors, including heredity, obesity, injury and joint overuse, are thought to contribute to the development of osteoarthritis (2, 3), the molecular mechanism underlying this disease is still elusive.Mitogen-inducible gene 6 (Mig-6), also known as gene 33, is an immediate early response gene that can be induced by many growth factors or stressful stimuli (4, 5). It has also been shown to act as a negative feedback inhibitor in EGF receptor signaling through direct interaction with EGF receptor family (5-7), and, similarly, the gene is induced by hepatocyte growth factor͞ scatter factor by means of the receptor tyrosine kinase Met (data not shown). To understand its role during mouse development and homeostasis, we generated Mig-6-deficient mice and demonstrated that Mig-6 is essential for normal joint maintenance and that loss of Mig-6 leads to early onset degenerative joint disease. Materials and MethodsMice and Genotyping. To generate Mig-6 knockout mice, we constr...

show abstract

Section: Resultsmentioning

confidence: 99%

Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease

Zhang

Lanning

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

112

View full text Add to dashboard Cite

show abstract

“…MMP13 is the main collagenase that cleaves type II collagen in articular cartilage leading to OA (Reboul et al 1996;Billinghurst et al 1997). Expression of a truncated form of TbRII (Serra et al 1997) or silencing Smad3 expression (Yang et al 1999) also results in an OA phenotype in mice, further showing the importance of TGF-b signaling in the maintenance of joint homeostasis. OA is observed in all characterized etiologies of LDS (mutations in TGFBR1, TGFBR2, SMAD3, and TGFB2), but appears to be particularly frequent in pa-…”

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

confidence: 99%

“…TGFb signaling controls longitudinal bone growth through inhibition of chondrocyte terminal differentiation and maintenance of the proliferating chondrocyte pool (Serra et al 1997;Alvarez et al 2001;Yang et al 2001;Alvarez and Serra 2004). Consequently, conditional inactivation of Tgfbr2 or Tgfbr1, which leads to ablation of TGF-b signaling, results in severe shortening of the limbs among other skeletal manifestations (Baffi et al 2004;Seo and Serra 2007;Matsunobu et al 2009;Hiramatsu et al 2011).…”

Section: Regulation Of Chondrogenesis and Longitudinal Bone Growth Bymentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

View full text Add to dashboard Cite

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.

show abstract

“…In an animal model of OA, TGF␤RII expression was shown to be dramatically decreased during advanced phases of the disease (17). In other studies, transgenic mice expressing a truncated TGF␤RII in skeletal tissue were shown to develop cartilage degenerative symptoms similar to that of OA in humans (18).…”

mentioning

confidence: 93%

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

Baugé

Legendre

Leclercq

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. Extracellular matrix deposition is tightly controlled by a network of regulatory cytokines. Among them, interleukin-1␤ (IL-1␤) and transforming growth factor ␤1 (TGF␤1) have been shown to play antagonistic roles in tissue homeostasis. The purpose of this study was to determine the influence of IL-1␤ on TGF␤ receptor type II (TGF␤RII) regulation and TGF␤1 responsiveness in human articular chondrocytes.Methods. TGF␤1-induced gene expression was analyzed through plasminogen activator inhibitor 1 and p3TP-Lux induction. Receptor-activated Smad (RSmad) phosphorylation, TGF␤ receptors, and Smad expression were determined by Western blotting and real-time reverse transcription-polymerase chain reaction techniques. Signaling pathways were investigated using specific inhibitors, messenger RNA (mRNA) silencing, and expression vectors.Results. IL-1␤ down-regulated TGF␤RII expression at both the protein and mRNA levels and led to inhibition of the TGF␤1-induced gene expression and Smad2/3 phosphorylation. Moreover, IL-1␤ strongly stimulated the expression of inhibitory Smad7.TGF␤RII overexpression abolished the loss of TGF␤1 responsiveness induced by IL-1␤. The decrease in TGF␤RII required de novo protein synthesis and involved both the NF-B and JNK pathways.Conclusion. We demonstrate that IL-1␤ impairs TGF␤1 signaling through down-regulation of TGF␤RII, which is mediated by the p65/NF-B and activator protein 1/JNK pathways, and secondarily through the up-regulation of Smad7. These findings show that there is cross-talk in the signaling of 2 regulatory cytokines involved in inflammation.

show abstract

Expression of a Truncated, Kinase-Defective TGF-β Type II Receptor in Mouse Skeletal Tissue Promotes Terminal Chondrocyte Differentiation and Osteoarthritis

Cited by 450 publications

References 69 publications

Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease

Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

Contact Info

Product

Resources

About