OBJECTIVE: In osteoarthritis (OA), a loss of healthy cartilage extracellular matrix (ECM) results in cartilage degeneration. Attracting chondrogenic progenitor cells (CPCs) to injury sites and stimulating them toward chondrogenic expression profiles is a regenerative approach in OA therapy. High mobility group box 1 protein (HMGB1) is associated with chemoattractant and proinflammatory effects in various pathological processes. Here, we investigate the migratory effects of HMGB1 in knee OA and CPCs for the first time. DESIGN: Immunohistochemistry, immunoblotting, and immunocytochemistry were performed to identify HMGB1 and its receptors, receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) in OA knee tissue, chondrocytes, and CPCs. In situ hybridization for HMGB1 mRNA was performed in CPCs ex vivo. The chemoattractant effects of HMGB1 on CPCs were analyzed in cell migration assays. RESULTS: HMGB1 expression in OA tissue and OA chondrocytes was higher than in healthy specimens and cells. HMGB1, RAGE, and TLR4 were expressed in CPCs and chondrocytes. In situ hybridization revealed HMGB1 mRNA in CPCs after migration into OA knee tissue, and immunohistochemistry confirmed HMGB1 expression at the protein level. Stimulation via HMGB1 significantly increased the migration of CPCs. CONCLUSIONS: Our results show the chemoattractant role of HMGB1 in knee OA. HMGB1 is released by chondrocytes and has migratory effects on CPCs. These effects might be mediated via RAGE and TLR4. The in vitro and ex vivo results of this study need to be confirmed in vivo.
OBJECTIVE: In osteoarthritis (OA), a loss of healthy cartilage extracellular matrix (ECM) results in cartilage degeneration. Attracting chondrogenic progenitor cells (CPCs) to injury sites and stimulating them toward chondrogenic expression profiles is a regenerative approach in OA therapy. High mobility group box 1 protein (HMGB1) is associated with chemoattractant and proinflammatory effects in various pathological processes. Here, we investigate the migratory effects of HMGB1 in knee OA and CPCs for the first time. DESIGN: Immunohistochemistry, immunoblotting, and immunocytochemistry were performed to identify HMGB1 and its receptors, receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4) in OA knee tissue, chondrocytes, and CPCs. In situ hybridization for HMGB1 mRNA was performed in CPCs ex vivo. The chemoattractant effects of HMGB1 on CPCs were analyzed in cell migration assays. RESULTS: HMGB1 expression in OA tissue and OA chondrocytes was higher than in healthy specimens and cells. HMGB1, RAGE, and TLR4 were expressed in CPCs and chondrocytes. In situ hybridization revealed HMGB1 mRNA in CPCs after migration into OA knee tissue, and immunohistochemistry confirmed HMGB1 expression at the protein level. Stimulation via HMGB1 significantly increased the migration of CPCs. CONCLUSIONS: Our results show the chemoattractant role of HMGB1 in knee OA. HMGB1 is released by chondrocytes and has migratory effects on CPCs. These effects might be mediated via RAGE and TLR4. The in vitro and ex vivo results of this study need to be confirmed in vivo.
Authors: R Kokkola; E Sundberg; A-K Ulfgren; K Palmblad; J Li; H Wang; L Ulloa; H Yang; X-J Yan; R Furie; N Chiorazzi; K J Tracey; U Andersson; H Erlandsson Harris Journal: Arthritis Rheum Date: 2002-10
Authors: Ingrid E Dumitriu; Paramita Baruah; Barbara Valentinis; Reinhard E Voll; Martin Herrmann; Peter P Nawroth; Bernd Arnold; Marco E Bianchi; Angelo A Manfredi; Patrizia Rovere-Querini Journal: J Immunol Date: 2005-06-15 Impact factor: 5.422
Authors: Ryan M Levy; Kevin P Mollen; Jose M Prince; David J Kaczorowski; Raghuveer Vallabhaneni; Shiguang Liu; Kevin J Tracey; Michael T Lotze; David J Hackam; Mitchell P Fink; Yoram Vodovotz; Timothy R Billiar Journal: Am J Physiol Regul Integr Comp Physiol Date: 2007-07-25 Impact factor: 3.619
Authors: V Boonyaratanakornkit; V Melvin; P Prendergast; M Altmann; L Ronfani; M E Bianchi; L Taraseviciene; S K Nordeen; E A Allegretto; D P Edwards Journal: Mol Cell Biol Date: 1998-08 Impact factor: 4.272