Regulation of α5 and αV Integrin Expression by GDF-5 and BMP-7 in Chondrocyte Differentiation and Osteoarthritis.

David Garciadiego-Cázares,Clemente Ibarra,Hilda I Aguirre-Sánchez,Juan B Kouri,René F Abarca-Buis,Cristina Velasquillo,Andre Van Wijnen

doi:10.1371/journal.pone.0127166

Abstract

The Integrin β1 family is the major receptors of the Extracellular matrix (ECM), and the synthesis and degradation balance of ECM is seriously disrupted during Osteoarthritis (OA). In this scenario, integrins modify their pattern expression and regulate chondrocyte differen-tiation in the articular cartilage. Members of the Transforming growth factor beta (Tgf-β) Su-perfamily, such as Growth differentiation factor 5 (Gdf-5) and Bone morphogenetic protein 7 (Bmp-7), play a key role in joint formation and could regulate the integrin expression during chondrocyte differentiation and osteoarthritis progression in an experimental OA rat model. Decrease of α5 integrin expression in articular cartilage was related with chondrocyte dedif-ferentiation during OA progression, while increase of α1, α2, and α3 integrin expression was related with fibrous areas in articular cartilage during OA. Hypertrophic chondrocytes expressedαV integrin and was increased in the articular cartilage of rats with OA. Integrin expression during chondrocyte differentiation was also analyzed in a micromass culture system of mouse embryo mesenchymal cells, micromass cultures was treated with Gdf-5 or Bmp-7 for 4 and 6 days, respectively. Gdf-5 induced the expression of theα5 sub-unit, while Bmp-7 induced the expression of the αV sub-unit. This suggests a switch in signaling for prehypertrophic chondrocyte differentiation towards hypertrophy, where Gdf-5 could maintain the articular chondrocyte phenotype and Bmp-7 would induce hypertrophy. Decrease of Ihh expression during late stages of OA in rat model suggest that the ossification in OA rat knees and endochondral ossification could be activated by Bmp-7 and αV integrin in absence of Ihh. Thus, chondrocyte phenotype in articular cartilage is similar to prehypetrophic chondrocyte in growth plate, and is preserved due to the presence of Indian hedgehog (Ihh), Gdf-5 and α5 integrin to maintain articular cartilage and prevent hy-pertrophy.

Highlights

Articular cartilage is a poorly regenerative tissue, and an injury in articular cartilage generally results in Osteoarthritis (OA) with the following three relevant characteristics: loss of synovial space; cartilage vascularization, and osteophyte formation [1,2]
We find that Indian hedgehog (Ihh) increase its expression in the earlier stages of OA, and at the late stages of OA decrease its expression in a similar way toα5 integrin expression, and articular cartilage rapidly differentiates into bone in a process like endochondral ossification in OA
This suggests that α5 integrin might play a relevant role in the maintenance of normal articular cartilage, but this is apparently contradictory, because it was reported that α5 integrin is necessary for the differentiation of prehypertrophic chondrocytes into the hypertrophic phenotype, articular cartilage does not undergo ossification in healthy individuals

Summary

Introduction

Articular cartilage is a poorly regenerative tissue, and an injury in articular cartilage generally results in Osteoarthritis (OA) with the following three relevant characteristics: loss of synovial space; cartilage vascularization, and osteophyte formation [1,2]. It has been recognized that the ligand for integrins α1-, α2-, α3-, and α10β1 is collagen, while for integrin α5β1 the ligand is fibronectin, and for α6β1, this is laminin [5] All of these integrins are expressed dynamically during chondrocyte differentiation [6,7,8,9,10,11]. Cartilage anlage, composed mainly of proliferating chondrocytes, becomes apparent in early limb budding, forming uninterrupted Y-shaped mesenchymal condensation, branches and the formation of a joint [18]. The interzone consists of compact and closely packed mesenchymal cells If any of these molecules are suppressed, joints are not formed. The α5β1 integrin is found in cartilage anlage, which is composed mainly of proliferating chondrocytes, but its expression is considerably inhibited at the interzone [16]. The presence of the α5β1 integrin in perichondrium and cartilage anlage promotes cell proliferation and chondrocyte differentiation to a prehypertrophic fate through members of the Bmp family, which induce the expression of Indian hedgehog (Ihh), a factor that promotes cell proliferation and chondrocyte prehypertrophy [21]

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Conclusion