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Systemic neutralization of TGF-? attenuates osteoarthritis.

ABSTRACT: Osteoarthritis (OA) is a major source of pain and disability worldwide with no effective medical therapy due to poor understanding of its pathogenesis. Transforming growth factor ? (TGF-?) has been reported to play a role in subchondral bone pathology and articular cartilage degeneration during the progression of OA. In this study, we demonstrated that systemic use of a TGF-?-neutralizing antibody (1D11) attenuates OA progression by targeting subchondral bone pathological features in rodent OA models. Systemic administration of 1D11 preserves the subchondral bone microarchitecture, preventing articular cartilage degeneration by inhibition of excessive TGF-? activity, in both subchondral bone and the circulation. Moreover, the aberrant increases in the numbers of blood vessels, nestin(+) mesenchymal stromal/stem cells, and osterix(+) osteoblast progenitors were normalized by 1D11 systemic injection. Thus, systemic neutralization of excessive TGF-? ligands effectively prevented OA progression in animal models, with promising clinical implications for OA treatment.

SUBMITTER: Xie L

PROVIDER: S-EPMC4970979 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Systemic neutralization of TGF-β attenuates osteoarthritis.

Xie Liang L Tintani Francis F Wang Xiao X Li Fengfeng F Zhen Gehua G Qiu Tao T Wan Mei M Crane Janet J Chen Qianming Q Cao Xu X

Annals of the New York Academy of Sciences 20160202 1

Osteoarthritis (OA) is a major source of pain and disability worldwide with no effective medical therapy due to poor understanding of its pathogenesis. Transforming growth factor β (TGF-β) has been reported to play a role in subchondral bone pathology and articular cartilage degeneration during the progression of OA. In this study, we demonstrated that systemic use of a TGF-β-neutralizing antibody (1D11) attenuates OA progression by targeting subchondral bone pathological features in rodent OA m ...[more]

PMID: 26837060

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Project description: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.

Dataset Information

Systemic neutralization of TGF-? attenuates osteoarthritis.

Publications

Systemic neutralization of TGF-β attenuates osteoarthritis.

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