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Halofuginone attenuates osteoarthritis by inhibition of TGF-? activity and H-type vessel formation in subchondral bone.

ABSTRACT: OBJECTIVES:Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models. METHODS:3-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 (?CT) and CT-based microangiography were quantitated to detect alterations of microarchitecture and vasculature in tibial subchondral bone. RESULTS:Halofuginone 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-? signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone. CONCLUSIONS:Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-? activity and aberrant angiogenesis as a potential preventive therapy for OA.

SUBMITTER: Cui Z

PROVIDER: S-EPMC5013081 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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

Cui Zhuang Z Crane Janet J Xie Hui H Jin Xin X Zhen Gehua G Li Changjun C Xie Liang L Wang Long L Bian Qin Q Qiu Tao T Wan Mei M Xie Min M Ding Sheng S Yu Bin B Cao Xu X

Annals of the rheumatic diseases 20151015 9

<h4>Objectives</h4>Examine whether osteoarthritis (OA) progression can be delayed by halofuginone in anterior cruciate ligament transection (ACLT) rodent models.<h4>Methods</h4>3-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. Immunostain ...[more]

PMID: 26470720

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Project description:Subchondral sclerosis is considered the main characteristic of advanced osteoarthritis, in which bone remodeling mediated by transforming growth factor ? (TGF?) signaling plays an indispensable role in the metabolism. Osteocytes have been identified as pivotal regulators of bone metabolism, due to their mechanosensing and endocrine function. Therefore, the aim of the present study was to investigate the association between osteocyte TGF? signal and subchondral sclerosis. Knee tibia plateau samples were collected from osteoarthritic patients and divided into three groups: The full cartilage, partial cartilage and full defect groups. Next, changes in osteocyte TGF? signaling and subchondral bone structure underlying various types of cartilage erosion were detected. Bone mineral density (BMD) assay, histology [hematoxylin and eosin, Safranin?O/Fast green, and tartrate resistant acid phosphatase (TRAP) staining], and reverse transcription?quantitative PCR mainly detected structural alterations, osteogenic and osteoclastic activity in the cartilage and subchondral bone. The activation of the TGF? signaling pathway in the subchondral bone was detected by immunohistochemistry and western blotting. The association between osteocyte TGF? and the regulation of bone metabolism was analyzed by correlation analysis, and further proven in vitro. It was confirmed that the BMD of the subchondral bone increased and underwent sclerosis in the partial cartilage and full defect groups. Additional observation included the thinning of the area of calcified cartilage, in which a bone island formed locally, with subchondral bone plate thickening and increased trabecular bone volume. TRAP staining suggested an increase in bone resorption in subchondral underlying areas of the partial cartilage and full defect groups. Immunohistochemistry results confirmed the activation of osteocyte TGF? in subchondral underlying areas with severe cartilage erosion. Moreover, osteocyte phosphorylated?Smad2/3 was positively correlated with subchondral BMD, alkaline phosphatase and osteopontin mRNA expression, but it was negatively correlated with TRAP+ cells. Furthermore, it was confirmed in vitro that osteocyte TGF? signaling could regulate the osteogenic and osteoclastic activity of the mesenchymal stem cells. This study illustrated that osteocyte TGF? signaling is positively associated with the remodeling of subchondral bone in advanced osteoarthritis and provides a preliminary theoretical basis for further investigations of the role and mechanism of osteocyte TGF? in subchondral of osteoarthritis.

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Halofuginone attenuates osteoarthritis by inhibition of TGF-? activity and H-type vessel formation in subchondral bone.

Publications

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

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