Inhibition of cyclooxygenase-2 activity in subchondral bone modifies a subtype of osteoarthritis

Abstract

Osteoarthritis (OA) causes the destruction of joints. Its pathogenesis is still under investigation, and there is no effective disease-modifying therapy. Here, we report that elevated cyclooxygenase-2 (COX-2) expression in the osteocytes of subchondral bone causes both spontaneous OA and rheumatoid arthritis (RA). The knockout of COX-2 in osteocytes or treatment with a COX-2 inhibitor effectively rescues the structure of subchondral bone and attenuates cartilage degeneration in spontaneous OA (STR/Ort) mice and tumor necrosis factor-α transgenic RA mice. Thus, elevated COX-2 expression in subchondral bone induces both OA-associated and RA-associated joint cartilage degeneration. The inhibition of COX-2 expression can potentially modify joint destruction in patients with arthritis.

Chondroprotective Actions of Selective COX-2 Inhibitors In Vivo: A Systematic Review

“…Next to surgically induced OA models, the monosodium iodoacetate (MIA) rat OA model [ 16 , 17 , 23 ], the collagenase OA model [ 13 , 19 ] and the spontaneous OA mouse model (STR/Ort) [ 21 ] were also used to investigate chondroprotective actions of selective COX-2 inhibitors celecoxib [ 13 , 16 , 17 , 19 , 21 ] and meloxicam [ 23 ]. In these studies, chondroprotective actions of selective COX-2 inhibitors were observed after oral administration as evidenced by improved histological scores compared to the controls.…”

“…Fourteen of the included studies have investigated chondroprotective actions of selective COX-2 inhibitors after systemic administration (Table 1). Most studies focused on chondroprotective actions of the selective COX-2 inhibitor celecoxib [12][13][14][15][16][17][18][19][20][21], while other studies investigated chondroprotective actions of meloxicam [22,23] and etoricoxib [24,25]. Four studies that investigated chondroprotective actions of selective COX-2 inhibitors in surgically induced OA models failed to demonstrate chondroprotective actions when the drug was administered directly after OA induction [12,14,18,22].…”

“…In conclusion, there is conflicting evidence regarding the chondroprotective actions of systemically administered selective COX-2 inhibitors since five studies did not show chondroprotective actions, while nine studies showed chondroprotective actions after systemic administration with selective COX-2 inhibitors. Next to surgically induced OA models, the monosodium iodoacetate (MIA) rat OA model [16,17,23], the collagenase OA model [13,19] and the spontaneous OA mouse model (STR/Ort) [21] were also used to investigate chondroprotective actions of selective COX-2 inhibitors celecoxib [13,16,17,19,21] and meloxicam [23]. In these studies, chondroprotective actions of selective COX-2 inhibitors were observed after oral administration as evidenced by improved histological scores compared to the controls.…”

The roles of osteocytes in alveolar bone destruction in periodontitis

“…It has been shown that conditioned medium from osteoclasts and vascular endothelial cells treated with conditioned medium from loaded osteocytes can inhibit the metastasis and promote the apoptosis of breast cancer cells [ 126 ]. In most RA and osteoarthritis (OA) patients, the expression of cyclooxygenase-2 (COX-2) in osteocytes is high [ 127 ]. Induced overexpression of osteocyte COX-2 caused spontaneous OA and transgenic RA, and exclusive knockout of Cox-2 in osteocytes attenuated joint cartilage degeneration [ 127 ].…”

“…In most RA and osteoarthritis (OA) patients, the expression of cyclooxygenase-2 (COX-2) in osteocytes is high [ 127 ]. Induced overexpression of osteocyte COX-2 caused spontaneous OA and transgenic RA, and exclusive knockout of Cox-2 in osteocytes attenuated joint cartilage degeneration [ 127 ]. The loss or mutation of DMP1 or phosphate-regulating gene with homologies to endopeptidases on the X chromosome (Phex), which are both highly expressed by osteocytes, can lead to upregulation of FGF23 in osteocytes and subsequent hypophosphatemia [ 128 , 129 ].…”