The Effect of Alpha-2 Macroglobulin on the Healing of Ruptured Anterior Cruciate Ligament in Rabbits

Demirağ, Burak; Sarısözen, Bartu; Durak, Kemal; Bilgen, Ömer Faruk; Öztürk, Çağatay

doi:10.1080/03008200490278115

Cited by 21 publications

(17 citation statements)

References 11 publications

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“…Studies have shown that A2M inhibits the activities of ADAMTS-4, ADAMTS-5, ADAMTS-7, and ADAMTS-12 [21, 22], reduces ligament stump resorption following ACL injury [15], and enhances tendon-bone healing of ACL grafts by inhibiting MMP-13 activity [16]. Thus, the balance of the protease/A2M in vivo may play an important role in mediating cartilage destruction by catabolic enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…Higher A2M concentration is associated with lower MMP-13 content [5]. The difference is thought to be due to the large molecular weight of A2M, which prevents it’s migration from the blood into the SF [14, 15]. Thus, supplemental A2M may be a potential strategy to attenuate cartilage degeneration by reducing these catabolic enzymes induced by joint injury.…”

Section: Discussionmentioning

confidence: 99%

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Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection

et al. 2017

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BackgroundThe study was performed to evaluate whether targeted alpha-2-macroglobulin (A2M) variants have a similar or enhanced function at wild-type (wt)-A2M to attenuate cartilage degeneration in vivo.MethodsIn and ex-vivo experiment, bovine cartilage explants (BCE) were incubated with TNF-α and IL-1β with or without wt-A2M or A2M variants. Cartilage catabolism was measured in culture supernatant by sulfated glycosaminoglycan (sGAG). In an in-vivo experiment, 2-month-old male Wistar rats (n = 77) were randomly divided into seven groups and treated with different doses of A2M or its variants by intra-articular injection at 24 hours and day 14 after anterior cruciate ligament transection (ACLT), receiving (1) ACLT/PBS; (2) ACLT/wt-A2M (0.153 mg); (3) ACLT/CYT-108 A2M (0.153 mg); (4) ACLT/CYT-108 A2M (0.077 mg); (5) ACLT/CYT-98 A2M (0.153 mg); (6) ACLT/CYT-98 A2M (0.077 mg); or (7) sham/PBS. The joints and synovial lavage were collected 8 weeks after surgery. Fluorescence molecular tomography was used to monitor inflammation in vivo using probes ProSense and MMPSense at 24 hours, and weeks 2, 4, and 6 after surgery. The cartilage damage was quantified using Osteoarthritis Research Society International score and matrix metalloproteinase (MMP)-3, -13, collagen (Col) X, Col 2, Runx2, and aggrecan (Acan) were detected by immunohistochemical analysis (IHC), ELISA, and RT-PCR.ResultsA2M variants inhibited catabolism in the BCE model by up to 200% compared with wt-A2M. ProSense and MMPSense were dramatically increased in all groups after surgery. Supplemental A2M or its variants reduced ProSense and MMPSense compared with the PBS treatment. Less cartilage damage, lower MMP-13 and Col 2 degraded product, and stronger Col 2 synthesis were detected in animals treated with A2M or its variants compared with PBS-treated animals. A2M and its variants enhanced Col 2 and Acan synthesis, and suppressed MMP-3, MMP-13, Runx2, and Col X production. A2M-108 variant demonstrated less cartilage damage compared with wt-A2M and A2M-98 variant.ConclusionThe targeted variants of A2M have a chondroprotective effect similar to wt-A2M. However, A2M-108 variant has enhanced function to attenuate cartilage degeneration compared with wt-A2M.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection

et al. 2017

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“…The same procedure was repeated on the first postoperative day. The dose of α 2 -macroglobulin used for the present study was based on previously reported histological results 19 .…”

Section: Methodsmentioning

confidence: 99%

Enhancement of Tendon-Bone Healing of Anterior Cruciate Ligament Grafts by Blockage of Matrix Metalloproteinases

Demirağ

Sarısözen

Özer

et al. 2005

J Bone Joint Surg Am

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“…High and low levels of A2M have been found in blood and synovial joints, respectively, due to the large molecular weight of A2M, which prevents its migration from blood into the synovial fluid (SF) . Thus, supplemental A2M may be a potential strategy to attenuate cartilage degeneration by reducing these catabolic enzymes induced by joint inflammation.…”

Section: Discussionmentioning

confidence: 99%

Early supplemental α2‐macroglobulin attenuates cartilage and bone damage by inhibiting inflammation in collagen II‐induced arthritis model

Chen

Wei

et al. 2019

Int J of Rheum Dis

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Objective:To determine if early supplemental intra-articular α2-macroglobulin (A2M) has a chondroprotective effect in a collagen II-induced arthritis (CIA) mice model. Methods: DBA/1 mice were randomized into four groups (n = 15/group): (a) CIA + 1.2 μg of A2M; (b) CIA + 0.8 μg of A2M; (c) CIA + 0.4 μg of A2M; (d) vehicle + phosphate-buffered saline (PBS). A2M was injected into right ankles and PBS was injected into the left ankles simultaneously as internal control at days 36, 43 and 50. The CIA inflammation clinical score and ankle thickness were recorded every other day starting on day 21 until sacrifice. Changes in inflammation were monitored by in vivo fluorescence molecular tomography (FMT). Inflammation, cartilage and bone damage were assessed with X-ray, histology and immunohistochemistry.Cartilage and inflammation-related gene expression was quantified by real-time polymerase chain reaction (PCR). Results:All mice showed ankle inflammation on day 33. After day 43, lower clinical scores, ankle thickness and Sharp/van der Heijde method scores in A2M-treated ankles compared with PBS-treated ankles. FMT data indicated that the inflammation markers MMPSense and ProSense were significantly elevated in the PBS-treated ankles than A2M-treated ankles. Histology and X-ray analyses indicated that A2M administration resulted in lower levels of inflammatory infiltration and synovial hyperplasia, as well as more typical cartilage and bone organization with increased COL II and Aggrecan staining when compared with PBS-treated ankles. In addition, real-time PCR showed that,matrix metalloproteinase-3, -9, -13, COL X and Runx2 were significantly less expressed in A2M-treated groups than PBS-treated animals. Conclusion:Early supplemental intra-articular A2M exerts an anti-inflammatory effect and attenuates cartilage and bone damage in a CIA model. K E Y W O R D Scartilage and bone damage, CIA, fluorescence molecular tomography, inflammation, α2macroglobulin | 655 LI et aL.

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The Effect of Alpha-2 Macroglobulin on the Healing of Ruptured Anterior Cruciate Ligament in Rabbits

Cited by 21 publications

References 11 publications

Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection

Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection

Enhancement of Tendon-Bone Healing of Anterior Cruciate Ligament Grafts by Blockage of Matrix Metalloproteinases

Early supplemental α2‐macroglobulin attenuates cartilage and bone damage by inhibiting inflammation in collagen II‐induced arthritis model

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