Synovial perlecan is required for osteophyte formation in knee osteoarthritis

Abstract

The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan-knockout mice (Hspg2−/−-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2−/−-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-β-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2−/−-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2−/−-Tgmice. The reduced osteophyte formation in Hspg2−/−-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF-β model, the osteophyte size and maturation were also significantly reduced in Hspg2−/−-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy.

Differentiation of osteophyte types in osteoarthritis – proposal of a histological classification

“…In OA, osteophytes usually develop on the outside of the cortical bone of the joint and originate from the periosteum [4]. The osteophyte development is triggered by various factors, for example mechanical factors, growth factors and cytokines that stimulate the proliferation of mesenchymal stem cells in the periosteum [5]. Inside the developing osteophyte, the cells undergo chondrogenesis and the mature hypertrophic chondrocytes are subsequently replaced with osteoblasts mediating bone formation [5].…”

Endorepellin Evokes Autophagy in Endothelial Cells

“…Perlecan is one of the few genes in the human genome that is expressed by both vascular (6 -9) and avascular tissues, such as cartilage (10), and is localized at the apical cell surface (11,12) as well as in the basement membranes of both epithelial and endothelial lined tissues (6,13,14). Based on its widespread expression in both embryonic (10) and adult (13) life and its ability to engage various receptor tyrosine kinases (15), perlecan regulates various biological processes, including cell adhesion (16), lipid metabolism (17), thrombosis (18), apoptosis (19), biomechanical properties of blood vessels and cartilage (20,21), premature rupture of fetal membranes (22), epidermal formation (23), endochondral bone (24) and enamel organ (25) formation, osteophyte formation (26), and corneal structure (27). Moreover, perlecan binds various growth factors (28 -32), and its expression is often deregulated in several types of cancer (33)(34)(35).…”

Bone Alterations in Painful Osteoarthritic Shoulder

“…However, the mechanism of osteophyte formation is largely unknown. Kaneko et al recently reported that Perlecan (Hspg2), a heparan sulfate proteoglycan, plays an important role in osteophyte development in OA using genetically-modified mice [14].…”