HIF-1α regulates osteoclastogenesis and alveolar bone resorption in periodontitis via ANGPTL4.

OBJECTIVE: The mechanism of alveolar bone resorption caused by periodontitis is not fully understood. We sought to investigate whether microenvironmental changes of local hypoxia are involved in these processes. METHODS: In this study, periodontitis models of control mice and knockout of Hypoxia Induced Factor 1α (HIF-1α) harboring Cathepsin K (CTSK) Cre mice were constructed to study the effect of osteoclasts affected by hypoxic environment on alveolar bone resorption. RAW264.7 cells were subsequently induced by CoCl2 to observe the effects of HIF-1α and Angiopoietin-like Protein 4 (ANGPTL4) on osteoblast differentiation and fusion. RESULTS: The degree of alveolar bone resorption in the periodontitis tissues was lesser in mice with conditional knockout of HIF-1α in osteoclasts than in wild-type mice. We also observed that HIF-1α conditional knockout mice had fewer osteoclasts on the alveolar bone surface than control mice. HIF-1α increases the expression of ANGPTL4 and promotes the differentiation of RAW264.7 cells into osteoblasts and cell fusion under chemically simulated hypoxic conditions. CONCLUSION: HIF-1α regulates osteoclastogenesis and participates in bone resorption in periodontitis through ANGPTL4.

HIF-1α regulates osteoclast activation and mediates osteogenesis during mandibular bone repair via CT-1.

OBJECTIVES: Hypoxia is one of the characteristics of microenvironmental changes after orthognathic surgery for fractures. HIF-1α is a main regulator of the hypoxic response and plays a crucial role in bone formation, remodelling, and homeostasis. Osteoclasts participate in bone absorption and affect osteogenesis, and osteoclasts differentiate in a path from the oxygen-rich bone marrow to oxygen-deficient bone lesions. Thus, we aimed to study the key functions of HIF-1α in osteoclasts during mandibular healing after osteotomy. MATERIALS AND METHODS: The function of HIF-1α in osteoclasts during fracture healing in osteoclast-specific HIF-1α-conditional-knockout mice was investigated in mandibular osteotomy. Primary osteoclasts were used to explore the expression of HIF-1α and cardiotrophin-1 (CT-1) at both the mRNA and protein levels. The ability of BMSCs co-cultured with conditioned media from osteoclast-specific HIF-1α-knockout primary osteoclasts was detected using osteoclast-mediated osteogenesis experiments. RESULTS: Hypoxia-inducible factor-1α increased osteoclastogenesis and bone resorption, and a delay in bone healing was found in osteoclast-specific HIF-1α-conditional-knockout mice compared with normal mice. HIF-1α-knockout primary osteoclasts inhibited bone resorption and CT-1 expression, and HIF-1α enhanced the osteoclast-mediated stimulation of BMSC differentiation by secreting CT-1. CONCLUSIONS: Hypoxia-inducible factor-1α can play a key role in the physiology and pathogenesis of bone resorption by promoting osteoclastogenesis during fracture and influencing osteogenesis through CT-1 during bone healing.

[Effect of zoledronic acid on mandibular socket healing process of mice at an early stage].

PURPOSE: To investigate how bisphosphonates affect early process of socket healing in mice model. METHODS: Eighteen 8-9 weeks C57BL/6 male mice were randomly divided into control and experimental group. Bisphosphonate-related osteonecrosis of the jaw（BRONJ）model was conducted by intraperitoneal injection of zoledronate（ZOL） and extraction of lower left first molar in mice. Three, five, seven day after surgery, the mice were sacrificed and paraffin-embedded slides were made. H-E staining was used to evaluate the gross condition. The distribution and amounts of osteoclasts were measured by TRAP staining. Finally, immunochemical staining was used to detect RUNX2 and CTSK level. All experiments were duplicated thrice, ImageJ was used for transformation of pictures and SPSS 20.0 software package was used for statistical analysis. RESULTS: In comparison with the control group, early process of socket healing in the experimental group was generally delayed. RUNX2,CTSK,TRAP expression level was decreased. On the whole, early bone remodeling process in ZOL injection group was suppressed. CONCLUSIONS: Zoledronic acid inhibited the migration of fibroblasts into socket, and reduced the expression of Runx2, hindering new bone formation. It also can reduce the expression of TRAP 3，5，7 days after tooth extraction and CTSK expression three days after operation, thus inhibiting the bone resorption function of osteoclasts.