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Ann Rheum Dis. 2016 Sep;75(9):1714-21. doi: 10.1136/annrheumdis-2015-207923. Epub 2015 Oct 15.

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

Author information

1
Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
2
Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
3
Department of Pharmaceutical Chemistry, Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA.
4
Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

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 (μCT) 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-β signalling to restore coupled bone remodelling and attenuating excessive angiogenesis in subchondral bone.

CONCLUSIONS:

Halofuginone attenuates OA progression by inhibition of subchondral bone TGF-β activity and aberrant angiogenesis as a potential preventive therapy for OA.

KEYWORDS:

Arthritis; Osteoarthritis; Treatment

PMID:
26470720
PMCID:
PMC5013081
DOI:
10.1136/annrheumdis-2015-207923
[Indexed for MEDLINE]
Free PMC Article

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