Objective NF-kappa B-dependent signaling is an important modulator in osteoarthritis (OA), and G protein-coupled receptor kinase 5 (GRK5) regulates the NF-kappa B pathway. This study was undertaken to investigate the functional involvement of GRK5 in OA pathogenesis. Methods GRK5 expression in normal and OA human knee joints was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed using human and mouse chondrocytes. OA was induced in GRK5-knockout mice by destabilization of the medial meniscus, and histologic examination was performed. OA was also induced in wild-type mice, which were then treated with an intraarticular injection of amlexanox, a selective GRK5 inhibitor, every 5 days for 8 weeks. Results GRK5 protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors and NF-kappa B transcriptional activation were down-regulated by suppression of the GRK5 gene in human OA chondrocytes (3.49-fold decrease in IL6 [P < 0.01], 2.43-fold decrease in MMP13 [P < 0.01], and 2.66-fold decrease in ADAMTS4 [P < 0.01]). Conversely, GRK5 overexpression significantly increased the expression of OA-related catabolic mediators and NF-kappa B transcriptional activation. On Western blot analysis, GRK5 deletion reduced I kappa B alpha phosphorylation (up to 4.4-fold decrease [P < 0.05]) and decreased p65 nuclear translocation (up to 6.4-fold decrease [P < 0.01]) in mouse chondrocytes. In vivo, both GRK5 deletion and intraarticular amlexanox protected mouse cartilage against OA. Conclusion Our results suggest that GRK5 regulates cartilage degradation through a catabolic response mediated by NF-kappa B signaling, and is a potential target for OA treatment. Furthermore, amlexanox may be a major compound in relevant drugs.
机构:
Columbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USAColumbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA
机构:
Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USAUniv Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
Bonizzi, G
Karin, M
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USAUniv Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
机构:Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Chen, Xiaoqing
Zhu, Huiling
论文数: 0引用数: 0
h-index: 0
机构:Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Zhu, Huiling
Yuan, Man
论文数: 0引用数: 0
h-index: 0
机构:Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Yuan, Man
Fu, Jie
论文数: 0引用数: 0
h-index: 0
机构:
Jiao Tong Univ, Hosp 6, Dept Radiat Oncol, Shanghai 200233, Peoples R ChinaFudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Fu, Jie
Zhou, Yuqing
论文数: 0引用数: 0
h-index: 0
机构:Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Zhou, Yuqing
Ma, Lan
论文数: 0引用数: 0
h-index: 0
机构:
Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R ChinaFudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
机构:
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Cheng, Shaowu
Li, Longxuan
论文数: 0引用数: 0
h-index: 0
机构:
Guangdong Med Coll Affiliated Hosp, Dept Neurol, Zhanjiang 524001, Peoples R China
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Li, Longxuan
He, Shuangteng
论文数: 0引用数: 0
h-index: 0
机构:
Kansas City Vet Affairs Med Ctr, Subst Abuse Res Lab, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
He, Shuangteng
Liu, Jun
论文数: 0引用数: 0
h-index: 0
机构:
Sun Yat Sen Univ, Affiliated Hosp 2, Dept Neurol, Guangzhou 510120, Guangdong, Peoples R China
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Liu, Jun
Sun, Yuning
论文数: 0引用数: 0
h-index: 0
机构:
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Sun, Yuning
He, Minchao
论文数: 0引用数: 0
h-index: 0
机构:
Ningxia Med Univ, Dept Biochem & Mol Biol, Ningxia 750004, Peoples R China
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
He, Minchao
Grasing, Kenneth
论文数: 0引用数: 0
h-index: 0
机构:
Kansas City Vet Affairs Med Ctr, Subst Abuse Res Lab, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Grasing, Kenneth
Premont, Richard T.
论文数: 0引用数: 0
h-index: 0
机构:
Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Premont, Richard T.
Suo, William Z.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Univ Kansas, Coll Med, Dept Physiol, Kansas City, KS 66170 USA
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
机构:
Columbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USAColumbia Univ, Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10032 USA
机构:
Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USAUniv Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
Bonizzi, G
Karin, M
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USAUniv Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, Sch Med, La Jolla, CA 92093 USA
机构:Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Chen, Xiaoqing
Zhu, Huiling
论文数: 0引用数: 0
h-index: 0
机构:Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Zhu, Huiling
Yuan, Man
论文数: 0引用数: 0
h-index: 0
机构:Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Yuan, Man
Fu, Jie
论文数: 0引用数: 0
h-index: 0
机构:
Jiao Tong Univ, Hosp 6, Dept Radiat Oncol, Shanghai 200233, Peoples R ChinaFudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Fu, Jie
Zhou, Yuqing
论文数: 0引用数: 0
h-index: 0
机构:Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
Zhou, Yuqing
Ma, Lan
论文数: 0引用数: 0
h-index: 0
机构:
Fudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R ChinaFudan Univ, State Key Lab Med Neurobiol & Pharmacol, Res Ctr, Shanghai Med Coll, Shanghai 200032, Peoples R China
机构:
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Cheng, Shaowu
Li, Longxuan
论文数: 0引用数: 0
h-index: 0
机构:
Guangdong Med Coll Affiliated Hosp, Dept Neurol, Zhanjiang 524001, Peoples R China
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Li, Longxuan
He, Shuangteng
论文数: 0引用数: 0
h-index: 0
机构:
Kansas City Vet Affairs Med Ctr, Subst Abuse Res Lab, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
He, Shuangteng
Liu, Jun
论文数: 0引用数: 0
h-index: 0
机构:
Sun Yat Sen Univ, Affiliated Hosp 2, Dept Neurol, Guangzhou 510120, Guangdong, Peoples R China
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Liu, Jun
Sun, Yuning
论文数: 0引用数: 0
h-index: 0
机构:
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Sun, Yuning
He, Minchao
论文数: 0引用数: 0
h-index: 0
机构:
Ningxia Med Univ, Dept Biochem & Mol Biol, Ningxia 750004, Peoples R China
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
He, Minchao
Grasing, Kenneth
论文数: 0引用数: 0
h-index: 0
机构:
Kansas City Vet Affairs Med Ctr, Subst Abuse Res Lab, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Grasing, Kenneth
Premont, Richard T.
论文数: 0引用数: 0
h-index: 0
机构:
Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Premont, Richard T.
Suo, William Z.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA
Univ Kansas, Coll Med, Dept Physiol, Kansas City, KS 66170 USA
Kansas City Vet Affairs Med Ctr, Lab Alzheimers Dis & Aging Res, Kansas City, MO 64128 USAUniv Kansas, Coll Med, Dept Neurol, Kansas City, KS 66170 USA