Pharmacologically targeting fatty acid synthase-mediated de novo lipogenesis alleviates osteolytic bone loss...

Pharmacologically targeting fatty acid synthase-mediated de novo lipogenesis alleviates osteolytic bone loss by directly inhibiting osteoclastogenesis through suppression of STAT3 palmitoylation and ROS signaling

AUTHORS

Chunmei Xiu, Lei Zhang, Chenxi Zhang, Yuannan Zhang, Xi Luo, Ziyi Zhang, Hangkai Zhao, Kaizhong Ji, Zhiyuan Chen, Guangxu He, Jianquan Chen

ABSTRACT

Aberrant increases in osteoclast formation and/or activity are the underlying cause of bone loss in a variety of osteolytic diseases. Fatty acid synthase (Fasn)-mediated de novo lipogenesis (DNL) is one of the major lipid metabolic pathways and has been shown to play critical roles in diverse physiological and pathological processes. However, little is known about its role in osteoclastogenesis. Here, we investigate the direct role of DNL in osteoclastogenesis and its therapeutic potential in osteolytic diseases. We found that Fasn expression and DNL levels are upregulated during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Inhibition of Fasn by shRNA knockdown or its pharmacological inhibitors (ASC40 and trans-C75) impairs osteoclast differentiation in vitro. Mechanistically, pharmacological inhibition of Fasn suppresses RANKL-induced c-Fos/NFATc1 expression and thus osteoclastogenesis partly by disrupting STAT3 palmitoylation, while promoting ROS scavenging to impair mitogen-activated protein kinase (MAPK) signaling. Finally, the therapeutic potential of ASC40 for the treatment of osteolytic bone loss is tested in two mouse models of osteolytic diseases, i.e. ovariectomy (OVX)-induced osteoporosis and titanium nanoparticle-induced calvarial osteolysis. The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated DNL is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases.

Targeting the osteoclastogenic cytokine IL-9 as a novel immunotherapeutic strategy in mitigating inflammatory bone loss in post-menopausal osteoporosis

AUTHORS

Leena Sapra, Chaman Saini, Shivani Sharma, Dibyani Nanda, Aishwarya Nilakhe, Naibedya Chattopadhyay, Avtar Singh Meena, Pradyumna K Mishra, Sarika Gupta, Bhavuk Garg, Vikrant Manhas, Rupesh K Srivastava

ABSTRACT

Recent discoveries have established the pivotal role of IL-9-secreting immune cells in a wide spectrum of inflammatory and autoimmune diseases. However, little is known about how IL-9 contributes to the etiology of inflammatory bone loss in PMO. We observed that IL-9 has a pathological impact on inflammatory bone loss in ovariectomized (Ovx) mice. Our in vivo temporal kinetics analysis revealed that estrogen deprivation enhanced the production of IL-9 from Th cells (majorly Th9 and Th17). Both our ex vivo and in vivo studies corroborated these findings in Ovx mice, as estrogen diminishes the potential of Th9 cells to produce IL-9. Mechanistically, Th9 cells in an IL-9-dependent manner enhance osteoclastogenesis and thus could establish themselves as a novel osteoclastogenic Th cell subset. Therapeutically neutralizing/blocking IL-9 improves bone health by inhibiting the differentiation and function of osteoclasts, Th9, and Th17 cells along with maintaining gut integrity in Ovx mice. Post-menopausal osteoporotic patients have increased IL-9-secreting Th9 cells, which may suggest a potential role for IL-9 in the development of osteoporosis. Collectively, our study identifies IL-9-secreting Th9 cells as a driver of bone loss with attendant modulation of gut-immune-bone axis, which implies IL-9-targeted immunotherapies as a potential strategy for the management and treatment of inflammatory bone loss observed in PMO.

Biomechanical and histomorphometric evaluation of biodegradable mini-implants for orthodontic anchorage in the mandible of beagle dogs

AUTHORS

Shuo Wang, Zuodong Zhao, Qingtao Zhang, Chang Liu

ABSTRACT

Objective

To evaluate the effectiveness of a mini-implant composed of unsintered hydroxyapatite, poly (L-lactic acid) and poly(lactic-co-glycolic acid) (u-HA/PLLA/PLGA) composites as an anchorage device under consistent orthodontic force (OF) loading in vivo.

Methods

An mandible model in beagle dogs was introduced. 144 mini-implants were implanted in both sides of the mandibles. The mini-implants in the experimental group (left side) were loaded at the magnitude of 200 g to simulate the OF. At 2, 4 and 6 months after implantation, tissue specimens were taken from the implanted sites and biomechanical, histological and histomorphometrical analysis were performed.

Results

Mini-implants in the group with the highest PLLA ratio showed a 27% non-fracture rate after 4 months and 20.83% after 6 months in beagle dogs, and the non-fractured mini-implants could maintain the tensile force of 200 g, while mini-implants in the other two groups were all fractured. Histomorphological analysis showed that there was no significant relationship between Bone Volume over Total Volume (BV/TV) and the implantation time among the most of the groups. The level of Bone-Implant Contact ratio (BIC) in Medium and Low ratio group were decreased gradually from 2 to 6 months.

Conclusions

This study showed the biodegradable mini-implant could work as an alternative to the titanium alloy mini-implant by adjusting the proportion of its ingredients.

Clinical relevance

Degradable mini-implants for orthodontic anchorage lie in their potential to revolutionize orthodontic treatments by offering a biodegradable alternative that minimizes the need for secondary surgeries for removal, thereby enhancing patient comfort and reducing overall treatment time.

Measuring bone metabolic activity in dialysis patients with renal osteodystrophy using [18F]-Sodium Fluoride positron emission tomography- comparison between static and dynamic measurements

AUTHORS

Louise Aaltonen, Niina Koivuviita, Marko Seppänen, Vesa Oikonen, Anna K. Kirjavainen, Heikki Kröger, Eliisa Löyttyniemi, Kaj Metsärinne

ABSTRACT

Background

Dynamic [18F]NaF PET has shown promising results in the measurement of bone metabolism in patients with renal osteodystrophy. Dynamic PET scans are challenging in clinical practice, and the objective of this study was to evaluate whether standardized uptake values measured by [18F]NaF PET could be a feasible method.

Methods

Twenty-eight patients on maintenance dialysis with confirmed renal osteodystrophy underwent a dynamic [18F]NaF PET scan. As a reference for bone metabolism, a bone biopsy was obtained from the anterior iliac crest (AIC). Tracer activity in bone was measured using Patlak analysis and standardized uptake values (SUV). SUV was also adjusted to tracer activity measured from the aorta 48–60 min after injection (SUVR).

Results

SUV measured in the lumbar spine (L1-L4) and at the AIC did not correlate with histomorphometric parameters obtained by bone biopsy. There was no statistically significant difference between SUV in different turnover groups. When adjusting the mean bone uptake of fluoride in the lumbar spine, there was a strong correlation with the blood clearance of tracer to bone (Ki). SUVR also correlated significantly with histomorphometric markers obtained by bone biopsy.

Conclusions

These results suggest that measurements of tracer activity in the blood 48–60 min after tracer injection could be used to correct SUVs from static [18F]NaF PET scans. However, further research and validation of the method is needed.

Catharanthine tartrate ameliorates osteoclastogenesis by destabilizing HIF-1α

AUTHORS

Luqiong Cai, Chenxin Yu, Binli Zhao, Qihang Wu, Haibo Liang, Meng Zhou, Jiansen Miao, Jiangtao Luo, Jiake Xu, Haiming Jin, Youjin Pan

ABSTRACT

With the aging population, postmenopausal osteoporosis (PMOP), clinically manifested by reduced bone density, weakened skeletal strength, and compromised skeletal microstructure, has become the most prevalent type. The decline in estrogen levels fosters oxidative stress and osteoclastogenesis, which significantly enhance the activity of osteoclasts. Current treatments prefer to adopt relevant strategies to inactivate osteoclasts but come with unavoidable side effects. In our study, Catharanthine Tartrate (CAT), a derivative of the alkaloid catharanthine found in Catharanthus roseus, promised to be an effective therapy for PMOP. CAT inhibited RANKL-induced osteoclast differentiation and bone resorption in vitro. Moreover, CAT inhibited osteoclast activity by enhancing the ubiquitination-mediated proteasomal degradation of HIF-1α, which reduced oxidative stress and subsequently suppressed osteoclast activity. The inhibitory effects of CAT on osteoclast function and oxidative stress were reversed by DMOG, a known inhibitor of HIF-1α degradation. Next, an in vivo mouse experiment using the Ovariectomized (OVX) model to induce osteoporosis indicated that CAT enhanced bone mass density, bone structure, and bone remodeling. Our findings revealed that CAT inhibits PMOP through facilitating HIF-1α ubiquitination and degradation, suggesting a promising therapeutic approach for this disorder.

Dimeric R25CPTH(1–34) activates the parathyroid hormone-1 receptor in vitro and stimulates bone formation in osteoporotic female mice

AUTHORS

Minsoo Noh, Xiangguo Che, Xian Jin, Dong-Kyo Lee, Hyun-Ju Kim, Doo Ri Park, Soo Young Lee, Hunsang Lee, Thomas J Gardella, Je-Yong Choi, Sihoon Lee

ABSTRACT

Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.