HIF-1α Mediates Osteoclast-Induced Mandibular Condyle Growth via AMPK Signaling

Abstract

During the mandibular condylar growth, the absorption of calcified cartilage matrix induced by osteoclasts is crucial for the continuous endochondral osteogenesis. Meanwhile, recent studies showed that subchondral bone resided within the low-oxygen microenvironment, and our previous study revealed that hypoxia-inducible transcription factor 1α (HIF-1α) promoted osteoclastogenesis under hypoxia. However, whether HIF-1α regulates the function of osteoclasts in the mandibular condyle cartilage remains elusive. Our study indicated that severe deformity of the mandibular condyle was displayed in 10-wk-old osteoclast-specific HIF-1α conditional knockout (CKO) mice, accompanied by shortened length of condylar process and disorganized fibrocartilage. In 1-, 2-, and 4-wk-old CKO mice, the size of the hypertrophic layer and chondrocytic layer was significantly thickened. In the chondrocytic layer, chondrocytes were atrophied, showing a form of apoptosis in 4-wk-old CKO mice. Furthermore, an increase in the thickness of the fibrous and proliferating layer was observed in 10-wk-old CKO mice, as well as a significant decrease in that of the chondrocytic and hypertrophic chondrocyte layers. Interestingly, the articular surface of the condylar process abnormally presented a horizontal concave shape, and a disk-like acellular connective tissue appeared. In addition, genetic ablation of HIF-1α blunted cartilage matrix loss by subchondral osteoclast deficiency, resulting in a high subchondral bone mass phenotype, accompanied with a decreased number of blood vessels, alkaline phosphatase staining, and vascular endothelial growth factor (VEGF) expression. Mechanistically, the number of osteoclasts in the center of the condyle in CKO mice was significantly reduced by attenuated expression of adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling. These findings reveal a novel influence of HIF-1α function in osteoclasts on maintenance of osteoclast-induced resorption of calcified cartilage matrix via AMPK signaling, as well as subchondral bone formation through VEGF-dependent angiogenesis in bone marrow.

Dimethyloxalylglycine Attenuates Steroid-Associated Endothelial Progenitor Cell Impairment and Osteonecrosis of the Femoral Head by Regulating the HIF-1α Signaling Pathway

“…This therapy potential collapsed after pretreatment with KC7F2, which was further confirmed by osteocalcin staining ( Figure 5 C,D). Nevertheless, some studies have noted that HIF-1α activation is closely related to osteoclast activity [ 45 , 46 ]; therefore, TRAP staining was performed to detect osteoclast activity. Unexpectedly, activated HIF-1α did not affect osteoclast activity, whereas the HIF-1α inhibitor hindered this effect ( Figure 5 E,F).…”

LncRNA-mRNA Expression Profiles of Osteoclast After Conditional Knockout HIF-1α

“…In vivo, we bred HIF-1αflox/flox; Ctsk cre + mice to specifically knock out HIF-1α in osteoclasts. We found that the condyle was abnormal, and this phenotype was thoroughly studied in our previous work (Tian et al, 2020;Tang et al, 2020). In this study, we isolated and cultured monocytes from CKO and Ctrl mice to induce osteoclast differentiation.…”

The onset of adenosine monophosphate‐activated protein kinase activity on orthodontic tooth movement in rats with type 2 diabetes

“…However, this ability to energy sense is impaired under hyperglycemia [16]. Additionally, studies have shown that changes of AMPK activity could affect periodontal inflammation and alveolar bone resorption [17][18][19][20][21]. Nevertheless, it remains unclear whether periodontal AMPK is inhibited under type 2 diabetes and how AMPK activity exactly influences orthodontic tooth movement.…”