Matrix metalloproteinases and their inhibitors in the foreign body reaction on biomaterials

Abstract

Matrix metalloproteinases (MMPs) can degrade structural components within the extracellular matrix and at the cellular surface producing changes in cellular behavior (i.e., adhesion and migration) and subsequent pathological responses (i.e., the foreign body reaction and wound healing). We continue to study the foreign body reaction that occurs following biomaterial implantation by investigating secretory responses of biomaterial-adherent macrophages and foreign body giant cells (FBGCs) as directed by material surface chemistry and further this research by determining whether secreted MMPs play a role in macrophage adhesion and fusion. We have identified numerous MMPs and their tissue inhibitors (TIMPs) in in vitro cell-culture supernatants using antibody arrays and quantified select MMP/TIMPs with ELISAs. MMP-9 concentrations were significantly greater than both TIMP-1 and TIMP-2 on all materials. The ratios of MMP-9/TIMP-1 and MMP-9/TIMP-2 increased with time because of an increase in MMP-9 concentrations over time, while the TIMP concentrations remained constant. Total MMP-9 concentrations in the supernatants were comparable on all materials at each timepoint, while TIMP-1 and TIMP-2 concentrations tended to be greater on hydrophilic/anionic surfaces. Analysis of the MMP/TIMP quantities produced per cell revealed that the hydrophilic/neutral surfaces, which inhibited macrophage adhesion, activated the adherent macrophages/FBGCs to produce a greater quantity of MMP-9, TIMP-1, and TIMP-2 per cell. Pharmacological inhibition of MMP-1,-8,-13, and -18 reduced macrophage fusion without affecting adhesion, while inhibitors of MMP-2,-3,-9, and -12 did not affect adhesion or fusion. These findings demonstrate that material surface chemistry does modulate macrophage/FBGC-derived MMP/TIMP secretion and implicates MMP involvement in macrophage fusion.

Lack of TNF-α–Induced MMP-9 Production and Abnormal E-Cadherin Redistribution Associated with Compromised Fusion in MCP-1–Null Macrophages

“…31 MMP-9 is expressed during human macrophage fusion in vitro. 32 Expression of MMP-9 in vitro during the fusion of peritoneal macrophages has also been reported. 10 Studies in MMP-9 -null mice suggested that this enzyme is critical for macrophage fusion and that it could also modulate several aspects of the foreign body response.…”

Adsorbed Fibrinogen Enhances Production of Bone- and Angiogenic-Related Factors by Monocytes/Macrophages

“…Consistent with this, enhanced secretion of matrix metaloproteinases (MMPs) and TIMPs by RGD-differentiated macrophages, as well as of more cytokine production by RGD-adherent dendritic cells, has been previously described. 48,49 We 22 and others 21 have recently reported that Ch is able to elicit an anti-inflammatory macrophage polarization. From a tissue-engineering perspective, induction of an antiinflammatory pro-regenerative macrophage phenotype is of key relevance, as reparative macrophages are crucial in tissue remodeling after inflammation, guiding the host response to implanted biomaterials.…”

“…57 As for TIMP-1 and TIMP-2, the high levels detected are in line with Ch-induced MMP9 secretion, 22 as TIMPs regulate MMP activity, and corroborate previous research work on MMPs/TIMPs production by biomaterial-adherent macrophages and FBCG. 48 Importantly, MMPs/TIMPs mediate many biological processes, namely inflammation, wound healing, and bone remodeling. 48,58 Regarding the pluripotent cytokine TGF-b1, it is required for bone formation 59,60 and fracture repair, 61 and plays a crucial role in bone turnover.…”

“…48 Importantly, MMPs/TIMPs mediate many biological processes, namely inflammation, wound healing, and bone remodeling. 48,58 Regarding the pluripotent cytokine TGF-b1, it is required for bone formation 59,60 and fracture repair, 61 and plays a crucial role in bone turnover. 62 In future in vivo studies, it would be interesting to investigate cytokine production at Ch-scaffold implant sites.…”

Гигантские Клетки Инородных Тел И Тканевые Реакции На Поверхности Имплантатов

“…Суть последнего состоит в закономер-ной конкурентной динамике обмена (адгезии и диссоциации) плазменных белков на поверхности имплантата в зависимости от их концентрации в плазме крови. Начальная последовательность ад-сорбции следующая: альбумин -иммуноглобу-лин G -фибриноген и фибронектин -фактор XII и высокомолекулярный кининоген [31,55]. При-сутствие в составе провизорного матрикса мито-генов, хемоаттрактантов, цитокинов, факторов роста и других биоактивных соединений опреде-ляет его модулирующий эффект на активность клеточных элементов, в том числе моноци-тов/макрофагов, и характер последующих отгра-ничительных реакций на биоматериалы.…”