Inhibition of Endogenous TGF-β During Experimental Osteoarthritis Prevents Osteophyte Formation and Impairs Cartilage Repair

Scharstuhl, Alwin; Glansbeek, Harrie L.; Beuningen, H.M. van; Vitters, E.L.; Kraan, P.M. van der; Berg, Wim B. van den

doi:10.4049/jimmunol.169.1.507

Cited by 216 publications

(170 citation statements)

References 36 publications

(36 reference statements)

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“…Ascorbate, in the presence of transition metal ions, is an extremely efficient activator of latent TGF␤, converting it to its active form (39). Active TGF␤ plays a key role in osteophyte formation (40). Furthermore, active TGF␤, injected into mouse knees or continuously overexpressed, leads to joint degeneration (41,42).…”

Section: Discussionmentioning

confidence: 99%

Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model

Kraus

Huebner

Stäbler

et al. 2004

Arthritis & Rheumatism

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Objective. To determine whether ascorbic acid might be of benefit for the treatment of spontaneous osteoarthritis (OA) when administered over a long period of time.Methods. We investigated the effects of 8 months' exposure to low, medium, and high doses of ascorbic acid on the in vivo development of histologic knee OA in the male Hartley guinea pig. The low dose represented the minimum amount needed to prevent scurvy. The medium dose was the amount present in standard laboratory guinea pig chow and resulted in plasma levels comparable with those achieved in a person consuming 200 mg/day (5 fruits and vegetables daily). The high dose was the amount shown in a previous study of the guinea pig to slow the progression of surgically induced OA.Results. We found an association between ascorbic acid supplementation and increased cartilage collagen content but, in contrast to findings in a previous study of surgically induced OA in the guinea pig, ascorbic acid worsened the severity of spontaneous OA. Active transforming growth factor ␤ (TGF␤) was expressed in marginal osteophytes, whose size and number were significantly increased with increasing intake of ascorbic acid. Synovial fluid levels of cartilage oligomeric matrix protein, a biomarker of cartilage turnover, corroborated the histologic findings.Conclusion. Ascorbic acid has been shown to activate latent TGF␤. Prolonged intraarticular exposure to TGF␤ has been shown to cause OA-like changes. We found expression of active TGF␤ in osteophytes, a prominent feature of the joint histology seen in association with ascorbic acid treatment. Thus, the deleterious effects of prolonged ascorbic acid exposure may be mediated in part by TGF␤. This worsening of OA with ascorbic acid supplementation suggests that ascorbic acid intake should not be supplemented above the currently recommended dietary allowance (90 mg/day for men and 75 mg/day for women).

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Section: Discussionmentioning

confidence: 99%

Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model

Kraus

Huebner

Stäbler

et al. 2004

Arthritis & Rheumatism

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“…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

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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...

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“…TGF-β1 and IGF-1 are also involved in matrix deposition and turnover, with TGF-β1 stimulating matrix synthesis, but, as mentioned above, leading to an abnormal type I collagen α chain ratio and collagenase activity, whereas IGF-1 inhibits matrix degradation in bone cells [70]. It is worth mentioning that a study in mice showed that intra-articular injections of TGF-β into the knee joint induced OA-like changes [71] and that blocking endogenous TGF-β production during experimental OA prevents osteophyte formation [72]. The localised effect of TGF-β and IGF-1 may be linked to an abnormal response to leptin by OA subchondral bone osteoblasts.…”

Section: Igf and Tgf-β1mentioning

confidence: 99%

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

Tat

Lajeunesse

Pelletier

et al. 2010

Best Practice & Research Clinical Rheumatology

151

121

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Over the past few decades, significant progress has been made with respect to new concepts about the pathogenesis of osteoarthritis (OA). This article summarises some of the knowledge we have today on the involvement of the subchondral bone in OA. It provides substantial evidence that changes in the metabolism of the subchondral bone are an integral part of the OA disease process and that these alterations are not merely secondary manifestations, but are part of a more active component of the disease. Thus, a strong rationale exists for therapeutic approaches that target subchondral bone resorption and/or formation, and data evaluating the drugs targeting bone remodelling raise the hope that new treatment options for OA may become available.

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Inhibition of Endogenous TGF-β During Experimental Osteoarthritis Prevents Osteophyte Formation and Impairs Cartilage Repair

Cited by 216 publications

References 36 publications

Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model

Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model

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

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

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