Local injection of halofuginone into the subchondral bone
relieves canine osteoarthritis by inhibiting transforming growth factor beta 1
signaling pathway

doi:10.3969/j.issn.2095-4344.2539

Abstract

Abstract:

BACKGROUND: Studies have shown that the increase of bone resorption in osteoclasts over-activates transforming growth factor beta 1 (TGF-β1), and uncouples bone resorption and bone formation, ultimately leading to a hardened phenotype of the subchondral bone in an animal model of osteoarthritis. Progression of osteoarthritis can be attenuated by inhibiting TGF-β1 signaling pathway.

OBJECTIVE: To detect whether osteoarthritis progression can be delayed by the local injection of halofuginone in Beagle models of osteoarthritis.

METHODS: Eighteen male Beagle dogs were randomized into a sham (control) group, a model (osteoarthritis) group, or a treatment (halofuginone) group. Animal models of osteoarthritis were made by anterior cruciate ligament transection in the latter two groups. Animals in the treatment group were given local injection of halofuginone (37.8 ng) into the subchondral bone. Serum levels of type II collagen C-terminal peptide (CTX-II) and type X collagen α1 chain (COL10A1) were measured at 4, 8, 12, and 16 weeks after modeling. The Beagle dogs were sacrificed at the 16th week after surgery, and the alterations of microarchitecture of the subchondral bone were detected by micro-CT. Articular cartilage degeneration was graded using safranin O and fast green staining combined with the Osteoarthritis Research Society International (OARSI)-modified Manking criteria. Immunostaining analyses were conducted to detect the expression levels of TGF-β1 and matrix metalloproteinase 13. The study protocol was approved by the Animal Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University, with the approval No. IACUC20160304-07.

RESULTS AND CONCLUSION: The COL10A1 level in the model group was higher than that in the control group and the treatment group at 8 and 12 weeks after modeling (P < 0.01). The levels of CTX-II in the model group were higher than that in the control group and the treatment group at 8, 12, and 16 weeks after modeling (P < 0.05). Micro-CT examination showed that compared with the control and treatment groups, the bone volume fraction of the subchondral bone was increased in the model group, while the subchondral bone trabecular separation and the trabecular model factor were decreased significantly (all P < 0.05). The OARSI-modified Manking score was significantly higher in the model group than in the control group and the treatment group (both P < 0.01). Immunohistochemistry results showed that the expression levels of matrix metalloproteinase 13 and TGF-β1 in the model group were significantly higher than those in the control group and the treatment group (all P < 0.01). No significant differences in the above-mentioned indexes were found between the control group and the treatment group (all P > 0.05). Overall, local injection of halofuginon attenuates anterior cruciate ligament transection-induced osteoarthritis by inhibiting abnormally elevated TGF-β1 in the subchondral bone and blocking abnormal bone remodeling. Therefore, local injection of halofuginon may be a new therapeutic alternative for osteoarthritis.

Key words: osteoarthritis, halofuginon, local injection, transforming growth factor beta 1, subchondral bone

CLC Number:

Ren Jiangdong, Shalitanati • Wuermanbieke, Nuerailijiang • Yushan, Wuhuzi • Wulamu, Cao Li. Local injection of halofuginone into the subchondral bone relieves canine osteoarthritis by inhibiting transforming growth factor beta 1 signaling pathway[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(14): 2147-2152.

Figures/Tables 10

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