This work was to investigate potential roles of HMGB1‐mediated ERK pathway in the healing process of bone fracture. Rat tibial fracture models were established and divided into control (rats with normal saline), HMGB1 (rats with HMGB1), and HMGB1+ PD98059 groups (rats with HMGB1 and 1 mg/kg of ERK1/2 inhibitor PD98059) with 30 rats per each. The healing of rats' fracture was observed by X‐ray films, the morphological changes of bone fractures by HE staining, the callus formation by micro‐CT and biomechanical test, and the expression of osteogenesis‐related genes, HMGB1 and ERK‐related proteins by qRT‐PCR and Western blot. Rats in the HMGB1 group was increased in X‐ray scores, peak torque, torsional stiffness, and the bone volume fraction (bone volume/total volume, BV/TV); meanwhile, those rats presented elevations in osteogenesis‐related genes and HMGB1 expressions, as well as p‐ERK/ERK ratio. However, rats in the HMGB1+ PD98059 group was significantly reduced in X‐ray score, peak torque, torsional stiffness, and BV/TV, as well as the expression of osteogenesis‐related genes and the ratio of p‐ERK/ERK, as compared to those from HMGB1 group. HMGB1 could promote the expressions of osteogenesis‐related genes and accelerate the healing process of fracture via activation of the ERK signaling pathway.

Osteoarthritis (OA) is a major degenerative disorder that affects the knee, and more than 33.6% of people aged over 65 years are affected by the disorder (O'Connor, 2006;Srikanth et al., 2005). The typical symptoms associated with OA include pain, swelling, stiffness, and loss of weight-bearing joint flexibility, all of which cast great burdens on patients' lives and the public health system. Currently, the most commonly used therapies for OA are those based on rehabilitation exercises and medication. However, these conventional therapies aim more at attenuating symptoms rather than providing curative treatment. Additionally, for patients with end-stage OA, joint replacement surgery is the only effective strategy, although the surgery itself comes with disadvantages such as high associated costs, perioperative complications, and infections (Gunaratne et al., 2017). Thus, the development of mild and effective methods of handling OA is highly solicited.

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We aim to identify the potential role of miR-296, which is a class of endogenous non-coding RNAs in regulating osteoblast differentiation. Human osteoblast cell line, hFOB 1.19 cells, were transfected with miR-296 overexpression or inhibition plasmid to upregulate or downregulate miR-296 expression, and then co-transfected with anti-Cbfal antibody to knockdown Cbfal. Alizarin red staining, alkaline phosphatase (ALP) activity, and enzyme-linked immunosorbent assay assays were performed to evaluate the extent of osteoblast differentiation. MTT assays were applied to measure cell proliferation. Wound healing and transwell assays were used to determine the ability of osteoblast migration and invasion. Flow cytometry assay was used to measure cell apoptosis and cell cycle change. The mRNA and protein expression of Cbfal, OSX, and Col-1 were confirmed by RT-qPCR and western blot respectively. We found that miR-296 overexpression contributed to a significant enhancement of matrix mineralization, ALP activity, and osteocalcin expression comparing with the negative control, whereas knockdown of miR-296 caused an opposite result. Meanwhile, the treatment of miR-296 promotes osteoblast migration, invasion, and proliferation, while it inhibits cell apoptosis. Compared with the negative control groups, the cells transfected with miR-296 also presented a much higher expression of Cbfal, OSX, and Col-1. Further experiments confirmed that the positive regulatory role of miR-296 in osteoblast differentiation is achieved by upregulating Cbfal expression. In conclusion, miR-296 promotes osteoblast differentiation by upregulating Cbfal expression in hFOB 1.19 cells, which may be used as a potential therapeutic target for the treatment of bone diseases in future.

No abstract