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J Tissue Eng Regen Med. 2018 Jan;12(1):e550-e565. doi: 10.1002/term.2325. Epub 2017 Apr 9.

Modulation of MMP-2 and MMP-9 through connected pathways and growth factors is critical for extracellular matrix balance of intra-articular ligaments.

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State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province, China.
Key Laboratory of Biorheological Science and Technology, Bioengineering College, Chongqing University, Chongqing, China.
Centre for Joint Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.


The healing mechanism of cruciate ligaments is not well elucidated. Crosstalk between adjacent tissues in the knee joint plays an important role in wound healing and tissue regeneration, but the gelatinase modulation in posterior cruciate ligament fibroblasts (PCLfs) and synovial cells (SCs) based on co-culture is still elusive. The present study sought to systematically elucidate the gelatinase modulation in both PCLfs and SCs based on in vitro co-culture and in a rabbit PCL-injury model in vivo. It was found that injured PCLfs and SCs can secrete high gelatinases after co-culture. Cytokines promote greater gelatinase secretion by both injured PCLfs and SCs in the form of monomers and dimers. Pathway inhibitors can reduce injury-induced gelatinase activities, but the presence of cytokines restores the higher activity. Inhibitor cocktails can reduce gelatinase expression to a normal level even in the presence of cytokines. Growth factors promote wound healing of the injured PCL by enhancing cell migration, proliferation and collagen synthesis, but also upregulate gelatinases. Modified inhibitor cocktails containing growth factor can also reduce gelatinase expression to a normal level. This gelatinase modulation was also verified in a rabbit PCL injury model in vivo. Together, the results aids understanding of the mechanism of gelatinase modulation in injured PCL ligament post-crosstalk with synovium and infers that the gelatinases could be a potential as a therapeutic target for acute ligament injury.


co-culture; cocktail therapy; gelatinase; growth factor; inflammatory factors; posterior cruciate ligament; signal pathway inhibitor; synovium

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