Impact of the SIK3 Pathway Inhibition on Osteoclast Differentiation via Oxidative Phosphorylation.

Maintenance of bone homeostasis and the balance between bone resorption and formation are crucial for maintaining skeletal integrity. This study sought to investigate the role of salt-inducible kinase 3 (SIK3), a key regulator in cellular energy metabolism, during the differentiation of osteoclasts. Despite osteoclasts being high energy-consuming cells essential for breaking down mineralized bone tissue, the specific function of SIK3 in this process remains unclear. To address this issue, we generated osteoclast-specific SIK3 conditional knockout mice and assessed the impact of SIK3 deletion on bone homeostasis. Our findings revealed that SIK3 conditional knockout mice exhibited increased bone mass and an osteopetrosis phenotype, suggesting a pivotal role for SIK3 in bone resorption. Moreover, we assessed the impact of pterosin B, a SIK3 inhibitor, on osteoclast differentiation. The treatment with pterosin B inhibited osteoclast differentiation, reduced the numbers of multinucleated osteoclasts, and suppressed resorption activity in vitro. Gene expression analysis demonstrated that SIK3 deletion and pterosin B treatment influence a common set of genes involved in osteoclast differentiation and bone resorption. Furthermore, pterosin B treatment altered intracellular metabolism, particularly affecting key metabolic pathways, such as the tricarboxylic acid cycle and oxidative phosphorylation. These results provide valuable insights into the involvement of SIK3 in osteoclast differentiation and the molecular mechanisms underlying osteoclast function and bone diseases.

Osteoporosis is a disease that causes bones to become weak and fragile, increasing the risk of fractures especially in elderly. It is caused by an imbalance between the formation of new bone and the destruction of old bone. Cells called osteoclasts are responsible for breaking down old bone. Excessive osteoclast activity results in bone loss and osteoporosis. Our research has identified a LKB1-SIK3 pathway, which acts as an energy sensor in osteoclasts. We found that this pathway is activated when osteoclast activity is increased, and we were able to reduce osteoclast activity by genetically removing or inhibiting SIK3. These findings suggest that targeting the LKB1-SIK3 pathway may be a promising new approach for the treatment of osteoporosis. Developing drugs that inhibit SIK3 may slow bone loss and reduce the risk of fractures in osteoporotic patients.

Association of Ligamentum Flavum Hypertrophy with Adolescent Idiopathic Scoliosis Progression-Comparative Microarray Gene Expression Analysis.

The role of the ligamentum flavum (LF) in the pathogenesis of adolescent idiopathic scoliosis (AIS) is not well understood. Using magnetic resonance imaging (MRI), we investigated the degrees of LF hypertrophy in 18 patients without scoliosis and on the convex and concave sides of the apex of the curvature in 22 patients with AIS. Next, gene expression was compared among neutral vertebral LF and LF on the convex and concave sides of the apex of the curvature in patients with AIS. Histological and microarray analyses of the LF were compared among neutral vertebrae (control) and the LF on the apex of the curvatures. The mean area of LF in the without scoliosis, apical concave, and convex with scoliosis groups was 10.5, 13.5, and 20.3 mm2, respectively. There were significant differences among the three groups (p < 0.05). Histological analysis showed that the ratio of fibers (Collagen/Elastic) was significantly increased on the convex side compared to the concave side (p < 0.05). Microarray analysis showed that ERC2 and MAFB showed significantly increased gene expression on the convex side compared with those of the concave side and the neutral vertebral LF cells. These genes were significantly associated with increased expression of collagen by LF cells (p < 0.05). LF hypertrophy was identified in scoliosis patients, and the convex side was significantly more hypertrophic than that of the concave side. ERC2 and MAFB genes were associated with LF hypertrophy in patients with AIS. These phenomena are likely to be associated with the progression of scoliosis.

Direct Reprogramming and Induction of Human Dermal Fibroblasts to Differentiate into iPS-Derived Nucleus Pulposus-like Cells in 3D Culture.

Intervertebral disc (IVD) diseases are common spinal disorders that cause neck or back pain in the presence or absence of an underlying neurological disorder. IVD diseases develop on the basis of degeneration, and there are no established treatments for degeneration. IVD diseases may therefore represent a candidate for the application of regenerative medicine, potentially employing normal human dermal fibroblasts (NHDFs) induced to differentiate into nucleus pulposus (NP) cells. Here, we used a three-dimensional culture system to demonstrate that ectopic expression of MYC, KLF4, NOTO, SOX5, SOX6, and SOX9 in NHDFs generated NP-like cells, detected using Safranin-O staining. Quantitative PCR, microarray analysis, and fluorescence-activated cell sorting revealed that the induced NP cells exhibited a fully differentiated phenotype. These findings may significantly contribute to the development of effective strategies for treating IVD diseases.