scholarly journals Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone

2015 ◽  
Vol 75 (9) ◽  
pp. 1714-1721 ◽  
Author(s):  
Zhuang Cui ◽  
Janet Crane ◽  
Hui Xie ◽  
Xin Jin ◽  
Gehua Zhen ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Subchondral Bone ◽  
Bone Remodelling ◽  
Cruciate Ligament ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Preventive Therapy ◽  
Protective Effects ◽  
Anterior Cruciate ◽  
Articular Cartilage Degeneration

ObjectivesExamine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models.Methods3-month-old male C57BL/6J (wild type; WT) mice and Lewis rats were randomised to sham-operated, ACLT-operated, treated with vehicle, or ACLT-operated, treated with halofuginone. Articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Immunostaining, flow cytometry, RT-PCR and western blot analyses were conducted to detect relative protein and RNA expression. Bone micro CT (μCT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone.ResultsHalofuginone attenuated articular cartilage degeneration and subchondral bone deterioration, resulting in substantially lower OARSI scores. Specifically, we found that proteoglycan loss and calcification of articular cartilage were significantly decreased in halofuginone-treated ACLT rodents compared with vehicle-treated ACLT controls. Halofuginone reduced collagen X (Col X), matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5) and increased lubricin, collagen II and aggrecan. In parallel, halofuginone-attenuated uncoupled subchondral bone remodelling as defined by reduced subchondral bone tissue volume, lower trabecular pattern factor (Tb.pf) and increased thickness of subchondral bone plate compared with vehicle-treated ACLT controls. We found that halofuginone exerted protective effects in part by suppressing Th17-induced osteoclastic bone resorption, inhibiting Smad2/3-dependent TGF-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone.ConclusionsHalofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.

Effect of Remnant-Preserving Reconstruction of Acute Anterior Cruciate Ligament Injuries in a Rabbit Model: Histological and Biomechanical Analysis

2022 ◽  
Vol 12 (5) ◽  
pp. 897-906
Author(s):  
XiaoChen Ju ◽  
Hao Chai ◽  
Sasirekha Krishnan ◽  
Abinaya Jaisankar ◽  
Murugan Ramalingam ◽  
...  
Keyword(s):  
Anterior Cruciate Ligament ◽  
Articular Cartilage ◽  
Acl Reconstruction ◽  
Bone Healing ◽  
Cruciate Ligament ◽  
Cartilage Degeneration ◽  
Remnant Preservation ◽  
Model Animal ◽  
Anterior Cruciate ◽  
Articular Cartilage Degeneration

Acute anterior cruciate ligament (ACL) is a key structure that stabilizes knee joints. The objective of this research is to investigate the influence of ligament remnants preserved on the tendon-bone healing following ACL reconstruction and to examine postoperative articular cartilage degeneration in rabbit as a model animal. Sixty New Zealand rabbits are randomly divided into an ACL reconstruction without remnant preservation group (Group A; n = 30) or ACL reconstruction with remnant preservation group (Group B; n = 30). The expression of HIF-1α, VEGF, and micro vessel density (MVD) in the transplanted tendon was detected by immunohistochemical staining at week 6 and 12 after the operation. The signal intensity of the transplanted tendon was observed by MRI scanning, and the width of the bone tunnel was measured by CT scanning at week 6 and 12 after the operation. The graft biomechanics was tested 12 weeks after the operation. The JNK and MMP-13 expression levels were compared to analyze the cartilage degeneration of the knee at week 12 after the operation. The experimental results were analyzed and showed that the remnant-preserving ACL reconstruction is beneficial for bone healing of the tendon in rabbits, but ACL reconstruction with or without ligament remnants preserved will not affect knee articular cartilage degeneration post-surgery.

Effect of Lubricin Mimetics on the Inhibition of Osteoarthritis in a Rat Anterior Cruciate Ligament Transection Model

2020 ◽  
Vol 48 (3) ◽  
pp. 624-634 ◽  
Author(s):  
Daniel Nemirov ◽  
Yusuke Nakagawa ◽  
Zhexun Sun ◽  
Amir Lebaschi ◽  
Susumu Wada ◽  
...  
Keyword(s):  
Anterior Cruciate Ligament ◽  
Articular Cartilage ◽  
Cruciate Ligament ◽  
Cartilage Degeneration ◽  
Histological Evaluation ◽  
Anterior Cruciate Ligament Transection ◽  
Friction Coefficients ◽  
Anterior Cruciate ◽  
Articular Cartilage Degeneration

Background: Lubricin, a mucinous glycoprotein, plays a chondroprotective role as a constituent of synovial fluid. Structural analogs have been synthesized to mimic the structure and function of native lubricin in an effort to recapitulate this effect with the goal of delaying progression of osteoarthritis (OA). Purpose: To investigate the efficacy of intra-articular injections of lubricin mimetics in slowing or preventing the progression of posttraumatic OA by using a rat anterior cruciate ligament transection model. Study Design: Controlled laboratory design. Methods: Four lubricin mimetics were investigated, differing from one another in their binding orientations and steric interactions. Eighty skeletally mature Sprague-Dawley rats underwent bilateral anterior cruciate ligament transections and were randomly allocated to receive intra-articular injections (50 µL/injection) of 1 of the 4 mimetics in the right knee and equal volumes of saline injection in the contralateral knee (control). All rats were euthanized 8 weeks postoperatively and assessed via biomechanical analysis, which evaluated comparative friction coefficients across the 4 groups, and histological evaluation of articular cartilage, osteophytes, and synovitis. The Osteoarthritis Research Society International (OARSI) histopathological assessment system was used to evaluate the degree of articular cartilage degeneration and osteophytes, while synovitis was assessed through a semiquantitative scoring system. Binding efficacy of the 4 mimetics was assessed in vitro and in vivo through the immunohistochemical localization of polyethylene glycol. Articular cartilage degeneration and synovitis scoring data analyses were performed with generalized estimating equation modeling. Results: Injection of the group 3 mimetic (random 24 + 400 + 30) directly correlated with improved OARSI scores for femoral articular cartilage degeneration when compared with saline-injected contralateral control knees ( P = .0410). No lubricin mimetic group demonstrated statistically significant differences in OARSI scores for tibial articular cartilage degeneration. Injection of the group 4 mimetic (AB 24 + 400 + 30) led to a statistically significant difference in osteophyte OARSI score ( P = .0019). None of the 4 lubricin mimetics injections incited an additive synovial inflammatory response. Immunohistochemical staining substantiated the binding capacity of all 4 mimetics, while in vivo experimentation revealed that the group 1 and 3 mimetics were still retained within the joint 4 weeks after injection. There were no differences in friction coefficients between any pair of groups and no significant trends based on lubricin mimetic structure. Conclusion: We demonstrated that the tribosupplementation of a traumatically injured knee with a specific lubricin structural analog may attenuate the natural progression of OA. Clinical Relevance: The current lack of efficacious clinical options to counter the onset and subsequent development of OA suggests that further investigation into the synthesis and behavior of lubricin analogs could yield novel translational applications.

scholarly journals Fargesin ameliorates osteoarthritis via macrophage reprogramming by downregulating MAPK and NF-κB pathways

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jiansen Lu ◽  
Hongbo Zhang ◽  
Jianying Pan ◽  
Zhiqiang Hu ◽  
Liangliang Liu ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Conditioned Medium ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Preventive Strategy ◽  
Protective Effects ◽  
Erk Mapk ◽  
Osteoarthritis Research Society ◽  
Main Components ◽  
Articular Cartilage Degeneration

Abstract Background To investigate the role and regulatory mechanisms of fargesin, one of the main components of Magnolia fargesii, in macrophage reprogramming and crosstalk across cartilage and synovium during osteoarthritis (OA) development. Methods Ten-week-old male C57BL/6 mice were randomized and assigned to vehicle, collagenase-induced OA (CIOA), or CIOA with intra-articular fargesin treatment groups. Articular cartilage degeneration was evaluated using the Osteoarthritis Research Society International (OARSI) score. Immunostaining and western blot analyses were conducted to detect relative protein. Raw264.7 cells were treated with LPS or IL-4 to investigate the role of polarized macrophages. ADTC5 cells were treated with IL-1β and conditioned medium was collected to investigate the crosstalk between chondrocytes and macrophages. Results Fargesin attenuated articular cartilage degeneration and synovitis, resulting in substantially lower Osteoarthritis Research Society International (OARSI) and synovitis scores. In particular, significantly increased M2 polarization and decreased M1 polarization in synovial macrophages were found in fargesin-treated CIOA mice compared to controls. This was accompanied by downregulation of IL-6 and IL-1β and upregulation of IL-10 in serum. Conditioned medium (CM) from M1 macrophages treated with fargesin reduced the expression of matrix metalloproteinase-13, RUNX2, and type X collagen and increased Col2a1 and SOX9 in OA chondrocytes, but fargesin alone did not affect chondrocyte catabolic processes. Moreover, fargesin exerted protective effects by suppressing p38/ERK MAPK and p65/NF-κB signaling. Conclusions This study showed that fargesin switched the polarized phenotypes of macrophages from M1 to M2 subtypes and prevented cartilage degeneration partially by downregulating p38/ERK MAPK and p65/NF-κB signaling. Targeting macrophage reprogramming or blocking the crosstalk between macrophages and chondrocytes in early OA may be an effective preventive strategy.

scholarly journals Fargesin ameliorates osteoarthritis via macrophage reprogramming by downregulating MAPK and NF-κB pathways

2021 ◽  
Author(s):  
Jiansen Lu ◽  
Hongbo Zhang ◽  
Jianying Pan ◽  
Zhiqiang Hu ◽  
Liangliang Liu ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Preventive Strategy ◽  
Protective Effects ◽  
Erk Mapk ◽  
M1 Macrophage ◽  
Osteoarthritis Research Society ◽  
Main Components ◽  
Articular Cartilage Degeneration

Abstract Background: To investigate the role and regulatory mechanisms of fargesin, one of the main components of Magnolia fargesii, in macrophage reprogramming and crosstalk across cartilage and synovium during osteoarthritis (OA) development.Methods: 10-week-old male C57BL/6 mice were randomized assigned to vehicle, collagenase-induced OA (CIOA) or CIOA with intra-articular fargesin treatment groups. Articular cartilage degeneration was evaluated using the Osteoarthritis Research Society International (OARSI) score. Immunostaining and western blot analyses were conducted to detect relative protein. Raw264.7 cells were treated with LPS or IL-4 to investigate the role of polarized macrophages. ADTC5 cells were treated with IL-1β and the cultured medium is collected to investigate the crosstalk between chondrocytes and macrophages.Results: Fargesin attenuated articular cartilage degeneration and synovitis, resulting in substantially lower Osteoarthritis Research Society International (OARSI) and synovitis scores. In particular, significantly increased M2 polarization and decreased M1 polarization in synovial macrophages were found in fargesin-treated CIOA mice compared to controls. This was accompanied by down-regulation of IL-6 and IL-1β and upregulation of IL-10 in serum. Although conditioned medium (CM) from the M1 macrophage treated with fargesin reduced the expression of matrix metalloproteinase-13, RUNX2, type X collagen and increased Col2a1 and SOX9 in OA chondrocytes, but fargesin alone could not affect chondrocyte catabolic processes. Moreover, fargesin exerted protective effects by suppressing p38/ERK MAPK and p65/NF-κB signaling. Conclusions: This study showed that fargesin switched the polarized phenotypes of macrophages from M1 to M2 subtypes and prevented cartilage degeneration partially by down-regulating p38/ERK MAPK and p65/NF-κB signaling. Targeting macrophage reprogramming or blocking the crosstalk between macrophages and chondrocytes in early OA may be an effective preventive strategy.

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