COMP-Ang1 accelerates chondrocyte maturation by decreasing HO-1 expression

Abstract

Endochondral ossification is essential for new bone formation and remodeling during the distraction stage. Endochondral ossification is attributed to chondrocyte maturation, which is induced by various factors, such as the cellular environment, gene transcription, and growth factor expression. Cartilage oligomeric matrix protein (COMP)-angiopoietin 1 (Ang1) is more soluble, stable, and potent than endogenous Ang1, and COMP-Ang1 treatment has osteogenic and angiogenic effects in an in vivo model of bone fracture healing. Although the osteogenic effects of COMP-Ang1 have been demonstrated, the precise mechanism by which COMP-Ang1 induces chondrocyte maturation and triggers endochondral ossification is not understood. Here, we investigated the possible mechanism by which COMP-Ang1 induces chondrocyte maturation. First, using a WST assay, we found that COMP-Ang1 is nontoxic in rat chondrocytes. Then, we isolated total RNA from COMP-Ang1-treated rat chondrocytes, and analyzed the decrease in chondrogenic gene expression and the increase in osteogenic gene expression using real-time RT-PCR. Gene and protein expression of heme oxygenase-1 (HO-1), which maintains chondrocytes in an immature stage, decreased in a dose-dependent manner upon COMP-Ang1 treatment. To clarify the relationship between HO-1 and COMP-Ang1 in chondrocyte maturation, we used cobalt protoporphyrin IX (CoPP IX), an HO-1 inducer, and tin protoporphyrin IX (SnPP-IX), an HO-1 inhibitor. Treatment with various combinations of CoPP IX, SnPP IX, and COMP-Ang1 confirmed that COMP-Ang1 accelerates chondrocyte maturation by reducing HO-1. In conclusion, our results suggest that COMP-Ang1 accelerates chondrocyte maturation by interacting with HO-1.

Carnosic acid attenuates cartilage degeneration through induction of heme oxygenase-1 in human articular chondrocytes

“…Enhancing the expression of antioxidant enzymes in articular chondrocytes is a potential therapeutic approach in OA (Cai et al, 2015; Koike et al, 2015; Takada et al, 2015). The expression of HO-1, a key mediator of antioxidant defense, decreases with aging in articular cartilage and menisci of mouse knees (Takada et al, 2015) , and decreased HO-1 accelerates chondrocyte hypertrophic differentiation and Runx2 expression (Kim et al, 2013). On the other hand, the constitutive expression of HO-1 in mouse chondrocytes and meniscus reduces severity of joint damage with aging (Ochiai et al, 2008; Takada et al, 2015).…”

Expression and regulation of Angiopoietins and their receptor Tie-2 in sika deer antler

“…Based on the expression pattern of VEGF and Ang-1 in antler cartilage, we conjectured that they might play a similar role of promoting new blood vessel invasion into cartilage and keeping chondrocytes survival. Meanwhile, Ang-1 might activate Tie-2 which was also highly expressed in antler chondrocytes, and further stimulate blood vessel invasion into hypertrophic zone of cartilage (Jing et al 2013 ; Kim et al 2013 ). On the contrary, Ang-2 was a naturally occurring antagonist of Ang-1 and could competitively inhibit Ang-1-induced activation of Tie-2 (Escobar et al 2004 ).…”

“…Ang is involved in the maturation, stabilization and remodeling of vessels (Toyama et al 2009 ). Four members of the Ang family have been discovered and the best studied are angiopoietin-1 (Ang-1) and Ang-2 which regulate the angiogenesis in the process of endochondral ossification and participate in cartilage vascularization and chondrocyte maturation (Jing et al 2013 ; Kim et al 2013 ). Ang-1 and Ang-2 exert their biological effects through activating or blocking the activation of their receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie-2).…”

In vivo response of heme-oxygenase-1 to metal ions released from metal-on-metal hip prostheses

“…The accumulation of metal ions is considered, together with other factors, responsible for the high failure rates of MoM big head hip devices. In a number of studies, the presence of these ions was associated with the induction of oxidative stress (32)(33)(34)(35)(36)(37)(38)(39)(40).…”

“…In vitro studies demonstrated that Co (II) dose-and time-dependently induces HMOX-1 expression in different cell lines (33,40). In addition, in vivo studies that demonstrated HMOX-1 induction by Co, were conducted predominantly in the seventies and eighties (36)(37)(38), while the most recent studies were conducted in animal models (32,34,35,39). In these studies Cr appears to exhibit a different role on HMOX-1, depending on whether it is in the Cr (III) or Cr (VI) form.…”