Disease modification and symptom relief in osteoarthritis using a mutated GCP-2/CXCL6 chemokine.
Disease modification and symptom relief in osteoarthritis using a mutated GCP-2/CXCL6 chemokine.
复制标题
DOI：
10.15252/emmm.202216218
复制
发表时间：
2023-01-11
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
我们发现趋化因子受体C-X-C基序趋化因子受体2（CXCR 2）对软骨稳态至关重要。在这里，我们揭示了CXCR 2配体粒细胞趋化蛋白2（GCP-2）的表达，在胚胎发育过程中，在预期的永久性关节软骨，但不是在骺软骨注定要被骨取代。GCP-2表达在成人关节软骨中保留。GCP-2功能丧失抑制细胞外基质产生。GCP-2处理促进体外软骨形成和体内植入裸鼠中的人软骨类器官。为了利用GCP-2的软骨形成活性，我们通过诱变糖胺聚糖结合序列破坏了其趋化活性，我们假设这是在内皮上形成GCP-2趋触梯度所必需的。这种突变版本（GCP-2-T）在体外和体内诱导跨内皮迁移的能力降低，而不影响通过AKT的下游受体信号传导和软骨形成活性。关节内腺病毒过表达GCP-2-T，而不是野生型GCP-2，减少了小鼠不稳定性诱导的骨关节炎中的疼痛和软骨丢失。我们建议GCP-2-T可用于骨关节炎的疾病改良。骨关节炎是最常见的残疾原因，导致关节软骨破裂，引起关节疼痛和丧失活动能力;然而，我们没有药物治疗来阻止或逆转其病程。
We showed that the chemokine receptor C‐X‐C Motif Chemokine Receptor 2 (CXCR2) is essential for cartilage homeostasis. Here, we reveal that the CXCR2 ligand granulocyte chemotactic protein 2 (GCP‐2) was expressed, during embryonic development, within the prospective permanent articular cartilage, but not in the epiphyseal cartilage destined to be replaced by bone. GCP‐2 expression was retained in adult articular cartilage. GCP‐2 loss‐of‐function inhibited extracellular matrix production. GCP‐2 treatment promoted chondrogenesis in vitro and in human cartilage organoids implanted in nude mice in vivo. To exploit the chondrogenic activity of GCP‐2, we disrupted its chemotactic activity, by mutagenizing a glycosaminoglycan binding sequence, which we hypothesized to be required for the formation of a GCP‐2 haptotactic gradient on endothelia. This mutated version (GCP‐2‐T) had reduced capacity to induce transendothelial migration in vitro and in vivo, without affecting downstream receptor signaling through AKT, and chondrogenic activity. Intra‐articular adenoviral overexpression of GCP‐2‐T, but not wild‐type GCP‐2, reduced pain and cartilage loss in instability‐induced osteoarthritis in mice. We suggest that GCP‐2‐T may be used for disease modification in osteoarthritis. Osteoarthritis, which is the most common cause of disability, leads to breakdown of the articular cartilage and causes joint pain and loss of mobility; however, we do not have a pharmacological treatment for arresting or reverting its course.
登录
查看更多内容
影响因子：
4.9
作者：
Blaney Davidson EN;van de Loo FA;van den Berg WB;van der Kraan PM
通讯作者：
van der Kraan PM
DOI：
10.1038/nrdp.2016.73
发表时间：
2016-10-13
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
Martel-Pelletier, Johanne;Barr, Andrew J;Pelletier, Jean-Pierre
通讯作者：
Pelletier, Jean-Pierre
DOI：
10.1073/pnas.1704958114
发表时间：
2017-11-21
影响因子：
11.1
作者：
Getschman, A. E.;Imai, Y.;Volkman, B. F.
通讯作者：
Volkman, B. F.
DOI：
10.1369/0022155420977971
发表时间：
2021-03
期刊：
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
影响因子：
--
作者：
Handel TM;Dyer DP
通讯作者：
Dyer DP
影响因子：
--
作者：
Little, C. B.;Barai, A.;Burkhardt, D.;Smith, S. M.;Fosang, A. J.;Werb, Z.;Shah, M.;Thompson, E. W.
通讯作者：
Thompson, E. W.