A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

Docagne, Fabián; Colloc’h, N.; Bougueret, Vanessa; Pagé, Martine; Paput, Jérôme; Tripier, Marina; Dutartre, Patrick; MacKenzie, Eric T.; Komesli, Sylviane; Vivien, Denis

doi:10.1074/jbc.m010915200

Cited by 13 publications

(14 citation statements)

References 51 publications

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“…As expected, sT␤RII-B.Fc or sT␤RII.Fc alone significantly bound 125 I-TGF-␤1 in a dose-dependent manner, whereas there was no significant binding to 125 I-TGF-␤2. Also, sT␤RI.Fc by itself did not bind either 125 I-TGF␤1, as has previously been reported (35), or 125 I-TGF-␤2. Next we mixed sT␤RII-B.Fc or sT␤RII.Fc at 10 and 50 ng together with 100 ng of sT␤RI.Fc in the presence of 125 I-TGF-␤2.…”

Section: St␤rii-bfc and St␤riifc Require St␤rifc Protein For Bindisupporting

confidence: 74%

In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

Babitt

Pirani

et al. 2004

Journal of Biological Chemistry

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Transforming growth factor ␤ (TGF-␤) ligands exert their biological effects through type II (T␤RII) and type I receptors (T␤RI). Unlike TGF-␤1 and -␤3, TGF-␤2 appears to require the co-receptor betaglycan (type III receptor, T␤RIII) for high affinity binding and signaling. Recently, the T␤RIII null mouse was generated and revealed significant non-overlapping phenotypes with the TGF-␤2 null mouse, implying the existence of T␤RIII independent mechanisms for TGF-␤2 signaling. Because a variant of the type II receptor, the type II-B receptor (T␤RII-B), has been suggested to mediate TGF-␤2 signaling in the absence of T␤RIII, we directly tested the ability of T␤RII-B to bind TGF-␤2. Here we show that the soluble extracellular domain of the type II-B receptor (sT␤RII-B.Fc) bound TGF-␤1 and TGF-␤3 with high affinity (K d values ‫؍‬ 31.7 ؎ 22.8 and 74.6 ؎ 15.8 pM, respectively), but TGF-␤2 binding was undetectable at corresponding doses. Similar results were obtained for the soluble type II receptor (sT␤RII.Fc). However, sT␤RII.Fc or sT␤RII-B.Fc in combination with soluble type I receptor (sT␤RI.Fc) formed a high affinity complex that bound TGF-␤2, and this complex inhibited TGF-␤2 in a biological inhibition assay. These results show that TGF-␤2 has the potential to signal in the absence of T␤RIII when sufficient TGF-␤2, T␤RI, and T␤RII or T␤RII-B are present. Our data also support a cooperative model for receptor-ligand interactions, as has been suggested by crystallization studies of TGF-␤ receptors and ligands. Our cell-free binding assay system will allow for testing of models of receptor-ligand complexes prior to actual solution of crystal structures.Transforming growth factor-␤ (TGF-␤) 1 represents a large superfamily of dimeric growth factors that include the TGF-␤s, inhibins, activins, Mullerian inhibiting substance, growth and differentiation factors, and bone morphogenetic proteins (BMPs) in mammals (1, 2). These cytokines play important roles in an array of processes such as growth, differentiation, and development (3). There are three TGF-␤ isoforms that share a high degree of homology and overlapping biological activities (4). However, distinct expression patterns and unique, isoform-specific phenotypes of the corresponding knockout mice demonstrate significant non-redundancy of TGF-␤ function (5-9).TGF-␤s exert their biological effects through three cell surface receptors designated as type I, II, and III (T␤RI, T␤RII, and T␤RIII) (2), all of which have been cloned (10 -13). In addition, the type II-B receptor (T␤RII-B), an alternatively spliced isoform of T␤RII containing an insert of 26 amino acids replacing Val 51 , has also been identified (14 -16). Type I and type II receptors have intracellular serine/threonine kinase domains, whereas the type III receptor has only a short intracellular domain. On binding of TGF-␤ ligands, constitutively active type II receptors recruit and phosphorylate type I receptors; the activated type I receptor kinase then interacts with and phosphorylates downstream signaling ...

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Section: St␤rii-bfc and St␤riifc Require St␤rifc Protein For Bindisupporting

confidence: 74%

In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

Babitt

Pirani

et al. 2004

Journal of Biological Chemistry

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“…On the other hand, definitive conclusions based on these results are limited, since artificial dimerization of the receptor may well underlie much of the cooperativity observed. An additional compromising aspect of these preparations was their homogeneity, which was not demonstrated by del Re et al 33 and questionable for the receptor produced by Docagne and co-workers, 41 since multiple high molecular mass species, likely disulfide-linked oligomers, were apparent in non-reducing SDS/polyacrylamide gels. In addition, this preparation of receptor extracellular domain had TGFb agonist, not antagonist activity as expected.…”

Section: Discussionmentioning

confidence: 94%

“…3,10 TbRII, the high-affinity receptor for TGFbs 1 and 3, has been shown to bind wedge-like between the fingertips on the distal end of the ligand homodimer. 15 Little is known regarding the mechanism by which TbRI is cooperatively recruited into the heterotetrameric receptor signaling complex, although two reports, one by Docagne et al 41 and another by del Re et al, 33 have shown that artificially dimerized, Fc-chimeric TbRI-ED cooperatively binds TGFb isoforms and Fc-chimeric TbRII-ED. On the one hand, these results are significant, since they provide experimental support for models of receptor assembly based on either direct 15 or indirect 21 interactions.…”

Section: Discussionmentioning

confidence: 99%

Assembly of TβRI:TβRII:TGFβ Ternary Complex in vitro with Receptor Extracellular Domains is Cooperative and Isoform-dependent

Zúñiga

Groppe

Cui

et al. 2005

Journal of Molecular Biology

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“…After 12 hours of incubation, supernatants were collected and frozen at Ϫ70°C. Active TGF␤ was measured as described previously by using the mink lung epithelial cell bioassay (25).…”

Section: Methodsmentioning

confidence: 99%

“…To test the potential mechanism for the osteophyte suppression, we examined the effect of ALN on the local release of active TGF␤ (Figure 7). Levels of active TGF␤ were measured in 24-hour-conditioned media derived from cultures of tibia plateaus or patellas obtained from rats subjected to ACLT, using the mink lung epithelial cell proliferation assay (25). This bioassay measured a combination of all TGF␤ isoforms.…”

Section: Aln Blocking Of the Recruitment Of Trappositive Cells To Ostmentioning

confidence: 99%

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

Hayami

Pickarski

Wesolowski

et al. 2004

Arthritis & Rheumatism

510

466

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Objective. It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation.Methods. Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 g/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor ␤ (TGF␤), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF␤.Results. ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dosedependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF␤, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. Conclusion. Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.Osteoarthritis (OA) is a degenerative joint disease characterized by pain, cartilage loss, and joint stiffness. Although OA has long been considered to be primarily a cartilage disorder associated with focal articular cartilage degradation, this disease is accompanied by well-defined changes in the subchondral and periarticular bone, including sclerosis and cyst and osteophyte formation (1). The importance of the bone changes in the initiation and progression of OA is still being debated. It has been suggested that increased subchondral bone stiffness reduces the ability to dissipate the load and distribute the strain generated within the joint. This increases peak dynamic forces in the overlying articular cartilage and can accelerate its damage over time (2). The functional integrity of the articular cartilage can therefore depend on the mechanical properties of the underlying bone. Accordingly, cartilage damage leads to full-thickness cartilage loss only upon repetitive loading over an already stiffened subchondral bone plate (3).Recent studies have demonstrated increased subchondral bone turnover accompanied by specific architectural changes in the subchondral trabecular bone in OA joints (4,5...

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A Soluble Transforming Growth Factor-β (TGF-β) Type I Receptor Mimics TGF-β Responses

Abstract: Transforming growth factor-␤ (TGF-␤

Cited by 13 publications

References 51 publications

In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

In the Absence of Type III Receptor, the Transforming Growth Factor (TGF)-β Type II-B Receptor Requires the Type I Receptor to Bind TGF-β2

Assembly of TβRI:TβRII:TGFβ Ternary Complex in vitro with Receptor Extracellular Domains is Cooperative and Isoform-dependent

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

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