Attenuation of cartilage pathogenesis in post-traumatic osteoarthritis (PTOA) in mice by blocking the stromal derived factor 1 receptor (CXCR4) with the specific inhibitor, AMD3100.
SDF-1 was found to infiltrate cartilage, decrease proteoglycan content, and increase MMP-13 activity after joint trauma. In this study, we tested the hypothesis that interference of the SDF-1/CXCR4 signaling pathway via AMD3100 can attenuate pathogenesis in a mouse model of PTOA. We also tested the predictive and confirmatory power of fluorescence molecular tomography (FMT) for cartilage assessment. AMD3100 was continuously delivered via mini-osmotic pumps. The extent of cartilage damage after AMD3100 or PBS treatment was assessed by histological analysis 2 months after PTOA was induced by surgical destabilization of the medial meniscus (DMM). Biochemical markers of PTOA were assessed via immunohistochemistry and in vivo fluorescence molecular tomography (FMT). Regression analysis was used to validate the predictive power of FMT measurements. Safranin-O staining revealed significant PTOA damage in the DMM/PBS mice, while the DMM/AMD3100 treated mice showed a significantly reduced response with minimal pathology. Immunohistochemistry showed that AMD3100 treatment markedly reduced typical PTOA marker expression in chondrocytes. FMT measurements showed decreased cathepsins and MMP activity in knee joints after treatment. The results demonstrate that AMD3100 treatment attenuates PTOA. AMD3100 may provide a viable and expedient option for PTOA therapy given the drug's FDA approval and well-known safety profile.
Department of Orthopaedics, Warren Alpert Medical School of Brown University/RIH, CORO West, Suite 402H, 1 Hoppin Street, Providence, Rhode Island, 02903.
Nathan P
NP
Thomas
Department of Orthopaedics, Warren Alpert Medical School of Brown University/RIH, CORO West, Suite 402H, 1 Hoppin Street, Providence, Rhode Island, 02903.|Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan, China.
Pengcui
P
Li
Department of Orthopaedics, Warren Alpert Medical School of Brown University/RIH, CORO West, Suite 402H, 1 Hoppin Street, Providence, Rhode Island, 02903.
Braden C
BC
Fleming
Department of Orthopaedics, Warren Alpert Medical School of Brown University/RIH, CORO West, Suite 402H, 1 Hoppin Street, Providence, Rhode Island, 02903.
Qian
Q
Chen
Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan, China.
Xiaochun
X
Wei
Department of Orthopaedic Surgery, Baoan Hospital of Southern Medical University, The 8th People's Hospital, Shenzhen, PR China.
Pan
P
Xiao-Hua
Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, PR China.
Gang
G
Li
Department of Orthopaedics, Warren Alpert Medical School of Brown University/RIH, CORO West, Suite 402H, 1 Hoppin Street, Providence, Rhode Island, 02903.|Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Key Lab of Bone and Soft Tissue Injury Repair, Taiyuan, China.
Lei
L
Wei
D000818:Animals; D001596:Benzylamines; D002358:Cartilage, Articular / Q000473:pathology; D000080027:Cyclams; D004353:Drug Evaluation, Preclinical; D005456:Fluorescent Dyes; D006571:Heterocyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007718:Knee Injuries / Q000150:complications*; D008297:Male; D008810:Mice, Inbred C57BL; D020370:Osteoarthritis, Knee / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014054:Tomography
D001596:Benzylamines; D000080027:Cyclams; D005456:Fluorescent Dyes; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor
FMT; SDF-1; articular cartilage; osteoarthritis