Abstract
Osteoarthritis (OA) is a common debilitating joint disorder worldwide without effective medical therapy. Articular cartilage and subchondral bone act in concert as a functional unit with the onset of OA. Halofuginone is an analog of the alkaloid febrifugine extracted from the plant Dichroa febrifuga, which has been demonstrated to exert inhibition of SMAD 2/3 phosphorylation downstream of the TGF-β signaling pathway and osteoclastogenesis. To investigate whether halofuginone (HF) alleviates OA after administration by oral gavage, 3-month-old male mice were allocated to the Sham group, vehicle-treated anterior cruciate ligament transection (ACLT) group, and HF-treated ACLT group. The immunostaining analysis indicated that HF reduced the number of matrix metalloproteinase 13 (MMP-13) and collagen X (Col X) positive cells in the articular cartilage. Moreover, HF lowered histologic OA score and prevented articular cartilage degeneration. The micro-computed tomography (μCT) scan showed that HF maintained the subchondral bone microarchitecture, demonstrated by the restoration of bone volume fraction (BV/TV), subchondral bone plate thickness (SBP.Th.), and trabecular pattern factor (Tb.Pf) to a level comparable to that of the Sham group. Immunostaining for CD31 and μCT based angiography showed that the number and volume of vessels in subchondral bone was restored by HF. HF administered by oral gavage recoupled bone remodeling and inhibited aberrant angiogenesis in the subchondral bone, further slowed the progression of OA. Therefore, HF administered by oral gavage could be a potential therapy for OA.
Highlights
Osteoarthritis (OA) is the most common degenerative condition of the weight-bearing joints, characterized by pain and loss of function (McAlindon et al, 2014)
The aim of the present study is to investigate the potential attenuation of OA progression by HF following administration by oral gavage in a rodent anterior cruciate ligament transection (ACLT) model, which may provide evidence to support the oral route as an alternative route of HF administration for potential clinical application
HF abrogated this phenomenon (29.25 ± 7.33%) to the level comparable to Sham group (25.26 ± 8.37%) (p > 0.05) (Figure 2). These results suggest that HF played a protective role against articular cartilage degeneration
Summary
Osteoarthritis (OA) is the most common degenerative condition of the weight-bearing joints, characterized by pain and loss of function (McAlindon et al, 2014). In Asia, knee joint OA affects an estimated 5.7 and 4.4% of men and 10.3 and 19.2% of women in China and Korea respectively (Tang et al, 2015; Lee and Kim, 2017). It’s been estimated that the cost of OA treatment is up to 25–50% of a country’s GDP. The annual average direct cost of OA management varies from $1,442 to $21,335 per person (Xie et al, 2016). Effective disease-modifying therapy for OA is still lacking, leaving pain management and joint replacement as the last option for end-stage OA (Bijlsma et al, 2011; Carr et al, 2012). The pathogenesis of OA is not well understood (van den Berg, 2011), and an improved understanding is greatly needed to develop preventative and effective therapeutic interventions for early-stage OA
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