The phytochemical plumbagin reciprocally modulates osteoblasts and osteoclasts

Abstract Bone metabolism is essential for maintaining bone mineral density and bone strength through a balance between bone formation and bone resorption. Bone formation is associated with osteoblast activity whereas bone resorption is linked to osteoclast differentiation. Osteoblast progenitors give rise to the formation of mature osteoblasts whereas monocytes are the precursors for multi-nucleated osteoclasts. Chronic inflammation, auto-inflammation, hormonal changes or adiposity have the potential to disturb the balance between bone formation and bone loss. Several plant-derived components are described to modulate bone metabolism and alleviate osteoporosis by enhancing bone formation and inhibiting bone resorption. The plant-derived naphthoquinone plumbagin is a bioactive compound that can be isolated from the roots of the Plumbago genus. It has been used as traditional medicine for treating infectious diseases, rheumatoid arthritis and dermatological diseases. Reportedly, plumbagin exerts its biological activities primarily through induction of reactive oxygen species and triggers osteoblast-mediated bone formation. It is plausible that plumbagin’s reciprocal actions – inhibiting or inducing death in osteoclasts but promoting survival or growth of osteoblasts – are a function of the synergy with bone-metabolizing hormones calcitonin, Parathormone and vitamin D. Herein, we develop a framework for plausible molecular modus operandi of plumbagin in bone metabolism.

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Changes in bone metabolism associated with exposure to industrial vibration

Russian Journal of Occupational Health and Industrial Ecology ◽

10.31089/1026-9428-2019-59-9-766-767 ◽

2020 ◽

pp. 766-766

Author(s):

A. V. Sukhova ◽

E. N. Kryuchkova

Keyword(s):

Bone Mineral Density ◽

Alkaline Phosphatase ◽

Bone Resorption ◽

Bone Formation ◽

Bone Metabolism ◽

Biochemical Markers ◽

Mineral Density ◽

Local Vibration ◽

Markers Of Bone Formation

The influence of general and local vibration on bone remodeling processes is investigated. The interrelations between the long - term exposure of industrial vibration and indicators of bone mineral density (T-and Z-criteria), biochemical markers of bone formation (osteocalcin, alkaline phosphatase) and bone resorption (ionized calcium, calcium/creatinine) were established.

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New Insights Into the Physiology of Bone Regulation: the Role of Neurohormones

Physiological Research ◽

10.33549/physiolres.932668 ◽

2014 ◽

pp. 421-427 ◽

Cited By ~ 5

Author(s):

I. ŽOFKOVÁ ◽

P. MATUCHA

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Bone Metabolism ◽

Bone Tissue ◽

Protective Effects ◽

Humoral Factors ◽

Stimulate Bone Formation ◽

Osteoblast Activity ◽

Beta 2

Bone metabolism is regulated by interaction between two skeletal cells – osteoclasts and osteoblasts. Function of these cells is controlled by a number of humoral factors, including neurohormones, which ensure equilibrium between bone resorption and bone formation. Influence of neurohormones on bone metabolism is often bimodal and depends on the tissue, in which the hormone is expressed. While hypothalamic beta-1 and beta-2-adrenergic systems stimulate bone formation, beta-2 receptors in bone tissue activate osteoclatogenesis and increases bone resorption. Chronic stimulation of peripheral beta-2 receptors is known to quicken bone loss and alter the mechanical quality of the skeleton. This is supported by the observation of a low incidence of hip fractures in patients treated with betablockers. A bimodal osteo-tropic effect has also been observed with serotonin. While serotonin synthetized in brain has osteo-anabolic effects, serotonin released from the duodenum inhibits osteoblast activity and decreases bone formation. On the other hand, both cannabinoid systems (CB1 receptors in the brain and CB2 in bone tissue) are unambiguously osteo-protective, especially with regard to the aging skeleton. Positive (protective) effects on bone have also been shown by some hypophyseal hormones, such as thyrotropin (which inhibits bone resorption) and adrenocorticotropic hormone and oxytocin, both of which stimulate bone formation. Low oxytocin levels have been shown to potentiate bone loss induced by hypoestrinism in postmenopausal women, as well as in girls with mental anorexia. In addition to reviewing neurohormones with anabolic effects, this article also reviews neurohormones with unambiguously catabolic effects on the skeleton, such as neuropeptide Y and neuromedin U. An important aim of research in this field is the synthesis of new molecules that can stimulate osteo-anabolic or inhibiting osteo-catabolic processes.

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Exosome: Function and Application in Inflammatory Bone Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6324912 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Yingkun Hu ◽

Yi Wang ◽

Tianhong Chen ◽

Zhuowen Hao ◽

Lin Cai ◽

...

Keyword(s):

Bone Resorption ◽

Bone Metabolism ◽

Bone Disease ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Osteoclast Differentiation ◽

Bone Diseases ◽

The Body ◽

Stress Factors ◽

Osteoblast Activity

In the skeletal system, inflammation is closely associated with many skeletal disorders, including periprosthetic osteolysis (bone loss around orthopedic implants), osteoporosis, and rheumatoid arthritis. These diseases, referred to as inflammatory bone diseases, are caused by various oxidative stress factors in the body, resulting in long-term chronic inflammatory processes and eventually causing disturbances in bone metabolism, increased osteoclast activity, and decreased osteoblast activity, thereby leading to osteolysis. Inflammatory bone diseases caused by nonbacterial factors include inflammation- and bone resorption-related processes. A growing number of studies show that exosomes play an essential role in developing and progressing inflammatory bone diseases. Mechanistically, exosomes are involved in the onset and progression of inflammatory bone disease and promote inflammatory osteolysis, but specific types of exosomes are also involved in inhibiting this process. Exosomal regulation of the NF-κB signaling pathway affects macrophage polarization and regulates inflammatory responses. The inflammatory response further causes alterations in cytokine and exosome secretion. These signals regulate osteoclast differentiation through the receptor activator of the nuclear factor-kappaB ligand pathway and affect osteoblast activity through the Wnt pathway and the transcription factor Runx2, thereby influencing bone metabolism. Overall, enhanced bone resorption dominates the overall mechanism, and over time, this imbalance leads to chronic osteolysis. Understanding the role of exosomes may provide new perspectives on their influence on bone metabolism in inflammatory bone diseases. At the same time, exosomes have a promising future in diagnosing and treating inflammatory bone disease due to their unique properties.

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Changes in Bone Metabolism and Structure in Primary Hyperparathyroidism

Acta Medica Bulgarica ◽

10.2478/amb-2020-0050 ◽

2020 ◽

Vol 47 (4) ◽

pp. 75-80

Author(s):

I. Yankova ◽

A. Shinkov ◽

R. Kovatcheva

Keyword(s):

Bone Resorption ◽

Primary Hyperparathyroidism ◽

Bone Formation ◽

Bone Metabolism ◽

Cortical Bone ◽

Mineral Density ◽

Trabecular Microarchitecture ◽

Duration Of Action ◽

Increased Risk ◽

Stimulation Of

AbstractParathyroid hormone (PTH) is a key regulator of bone turnover. Depending on the duration of action, the hormone causes catabolic and anabolic effects by binding with specific receptors (PTHR1) in the bone. Various cells expressing PTHR1 on their surface are involved in the process – osteoblasts, osteocytes, bone marrow stromal cells, T-lymphocytes and macrophages. In physiological conditions PTH balances the bone metabolism. Intermittent pharmacological doses of PTH lead to the prevalence of bone formation and are used in the treatment of osteoporosis. Persistently elevated levels of PTH stimulate bone resorption by impacting mainly the cortical bone. New imaging and analysis techniques show that high PTH levels can also have an adverse effect on trabecular microarchitecture. Primary hyperparathyroidism (PHPT) is a disease characterized by increased bone metabolism, decreased bone mineral density (BMD), inadequate osteoid mineralization and an increased risk of fractures. Prolonged overproduction of PTH leads to stimulation of bone resorption and defects in bone formation, mainly causing loss of cortical bone mass, while in the trabecular bone predominate demineralization processes. One explanation of these findings is the enhanced stimulation of RANKL expression by osteoblasts with decreased OPG expression and bone formation at the same time.

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Bone Metabolism Markers in Sportswomen with Menstrual Cycle Dysfunctions

Journal of Medical Biochemistry ◽

10.2478/v10011-011-0012-8 ◽

2011 ◽

Vol 30 (2) ◽

pp. 135-140 ◽

Cited By ~ 2

Author(s):

Nenad Ponorac ◽

Nela Rašeta ◽

Dragan Radovanović ◽

Amela Matavulj ◽

Jelena Popadić-Gaćeša

Keyword(s):

Menstrual Cycle ◽

Bone Resorption ◽

Bone Formation ◽

Bone Metabolism ◽

Control Group ◽

Primary Amenorrhea ◽

Bone Resorption Marker ◽

Mineral Density ◽

Bone Metabolism Markers ◽

Significant Difference

Bone Metabolism Markers in Sportswomen with Menstrual Cycle DysfunctionsIt is a well known fact that sportswomen with irregular menstrual cycle are exposed to the risk of diminished bone mineral density, and consequentially osteoporosis may appear. Monitoring of the levels of biochemical markers of bone metabolism enables understanding of the dynamic changes during the bone remodeling process. The objectives of the conducted research were to determine the prevalence of menstrual dysfunctions in a sports-women sample and a control group, and also to determine the levels of bone metabolism markers in groups of women with menstrual dysfunctions. The women (n=117) were separated into two groups, the experimental group (S) (n=84) comprised of three subgroups of sports women (34 women who play ball game sports, 27 athletes and 23 sport dancers) and the control group (C) (n=34). To establish the menstrual profile and dysfunction of the menstrual cycle, we used a very detailed questionnaire. The level of mid-fragment osteocalcin (N-MID osteocalcin) as a marker of bone formation was deter mined, as well as β-Cross Laps (β-CTx-bone resorption marker) via the electro luminescent immunochemistry method on an Elecsys 1010 automated machine. Primary amenorrhea was found in 7 (8.33%) and oligomenorrhea in 11 (13.09%) sportswomen, which was statistically a much higher incidence (p<0.05) than in the control group (0/34). Values of bone metabolism markers showed a statistically significant difference in the level of the bone resorption marker β-CrossLaps between the groups of amenorrheic and oligomenorrheic sportswomen in comparison to the eumenorrheic women, both sportswomen and those in the control group. Accelerated resorption was accompanied with accelerated bone formation. Menstrual dysfunctions were statistically more present in the sports-women group than in the control group and were accompanied with accelerated bone metabolism from the point of view of the increase of bone metabolism markers level.

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Effects of Lemon Beverage Containing Citric Acid with Calcium Supplementation on Bone Metabolism and Mineral Density in Postmenopausal Women: Double-Blind 11-Month Intervention Study

Journal of Nutrition and Metabolism ◽

10.1155/2021/8824753 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Hiromi Ikeda ◽

Tadayuki Iida ◽

Masanori Hiramitsu ◽

Takashi Inoue ◽

Satomi Aoi ◽

...

Keyword(s):

Citric Acid ◽

Bone Resorption ◽

Bone Formation ◽

Bone Metabolism ◽

Postmenopausal Women ◽

Controlled Study ◽

Control Group ◽

Tartrate Resistant Acid Phosphatase ◽

Mineral Density ◽

Double Blind

A critical factor for preventing osteoporosis after menopause is attenuation of the accelerated turnover rate of bone metabolism. The present randomized controlled study was conducted to clarify the effects of a lemon beverage with calcium (Ca) supplementation that makes use of the chelating action of citric acid. Comprehensive evaluations of bone were performed by assessments of bone mineral density (BMD) and biomarkers related to bone turnover. Seventy-nine postmenopausal women were enrolled and asked to participate in an 11-month continuous intake of the test beverages. The subjects were divided into three groups: those who consumed a lemon beverage containing citric acid with Ca supplementation (LECA group), those who consumed a lemon beverage containing citric acid without Ca supplementation (LE group), and those who consumed no test beverage (control group). Using a double-blind protocol, subjects in the LECA and LE groups consumed one bottle containing 290 mL of the test beverage each day. The ratio of change in BMD after 11 months was significantly higher in the LECA group as compared to the control and LE groups. The LECA group also showed significant decreases in concentrations of tartrate-resistant acid phosphatase 5b (TRACP-5b), a bone resorption marker, and bone alkaline phosphatase (BAP) as compared to the other groups, as well as a significant decrease in concentration of osteocalcin (OC), a bone formation marker, as compared to the LE group. Based on our findings, we speculated that bone resorption and bone formation in postmenopausal women might be suppressed along with an increase in Ca resorption caused by chelation of citric acid in association with continuous ingestion of a Ca-supplemented lemon beverage containing citric acid, resulting in suppression of high bone metabolic turnover. In addition, the results provide information regarding BMD maintenance in the bones of the trunk, including the lumbar spine and proximal femur.

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Results of study of biochemical markers of bone metabolism in men with coronary heart disease

Medical alphabet ◽

10.33667/2078-5631-2020-15-39-43 ◽

2020 ◽

pp. 39-43

Author(s):

A. V. Voronkina ◽

T. A. Raskina ◽

M. V. Letaeva ◽

Yu. V. Averkieva ◽

O. S. Malyshenko ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Bone Formation ◽

Bone Metabolism ◽

Biochemical Markers ◽

Coronary Atherosclerosis ◽

Cathepsin K ◽

Arterial Calcification ◽

Mineral Density ◽

Bone Remodeling Markers

The development of atherosclerosis is closely related to the calcification of the vessel intima and fibrous plaques, being a complex and multifactorial process, in which the markers of bone formation and resorption play an important role. Objective. To study the biochemical markers of bone metabolism in men with stable coronary heart disease (CHD). Material and methods. The study included 102 men with verified CHD. Data were evaluated by densitometry, coronary angiography, multispiral computed tomography, color duplex scanning of brachiocephalic arteries, serum lipids (total cholesterol, triglycerides [TG], high-density [LHD] and low-density lipoprotein cholesterol), concentrationsin the blood of osteocalcin (OC), bone alkaline phosphatase (BAP), cathepsin K and C-telopeptides (CTx). Results. Concentrations of BAP, cathepsin K and CTx in patients with CHD were significantly higher than in men without CHD. The concentration of OC in men with normal bone mineral density was significantly lower than in patients with osteopenic syndrome. There was a direct correlation between OC and antiatherogenic HDL cholesterol and the inverse correlation between OC and TG, CTx and TG. There was no correlation between the level of bone remodeling markers and coronary artery (CA) lesion variant and the severity of coronary atherosclerosis on SYNTAX scale. The correlation analysis did not reveal the connection of biochemical markers of bone metabolism with the severity of coronary atherosclerosis and calcification and thickness of intima-media complex of carotid arteries. Absolute values of bone formation indices (BAP, OC) were significantly higher in patients with severe СA calcification than in patients without signs of calcification. Summary. Increased rates of osteogenesis and osteoresorption characterize the accelerated process of bone metabolism and indicate in favor of high rates of bone loss in men with CHD, which confirms the likelihood of common pathophysiological mechanisms of bone resorption and arterial calcification.

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The changes in bone turnover markers of female systemic lupus erythematousus patients without glucocorticoid

Lupus ◽

10.1177/09612033211000126 ◽

2021 ◽

Vol 30 (6) ◽

pp. 965-971

Author(s):

Wang Tianle ◽

Zhang Yingying ◽

Hong Baojian ◽

Gu Juanfang ◽

Wang Hongzhi ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Bone Turnover ◽

Bone Metabolism ◽

Bone Turnover Markers ◽

Control Group ◽

Bone Resorption Marker ◽

Amino Terminal ◽

Normal People ◽

Turnover Markers

Objectives SLE is a chronic autoimmune disease, which can affect the level of bone metabolism and increase the risk of osteoporosis and fracture. The purpose of this research is to study the effect of SLE on bone turnover markers without the influence of glucocorticoids. Methods A total of 865 female subjects were recruited from Zhejiang Provincial People’s Hospital and the First Hospital of Jiaxing, including 391 SLE patients without the influence of glucocorticoids and 474 non-SLE people. We detected Bone turnover markers including amino-terminal propeptide of type 1 procollagen (P1NP), C-terminal turnover of β - I collagen (β-CTX), N-terminal midfragment of osteocalcin (NMID) and 25(OH)D, and analyzed the difference in Bone turnover markers between the SLE group and the control group, as well as the influence of age and season on bone metabolism in female SLE patients. Results In the SLE group, the average age was 43.93±13.95 years old. In the control group, the average age was 44.84±11.42 years old. There was no difference between the two groups (t = 1.03, P = 0.30). P1NP, NMID and 25(OH)D in the SLE group were significantly lower than those in the control group (Z = 8.44, p < 0.001; Z = 14.41, p < 0.001; Z = 2.19, p = 0.029), and β-CTX in the SLE group was significantly higher than that in the control group (Z = 2.61, p = 0.009). In addition, the levers of β-CTX, NMID, P1NP and 25(OH)D in older SLE female patients were statistically significantly higher than those in younger (ρ = 0.104, p = 0.041; ρ = 0.223, p < 0.001; ρ = 0.105, p = 0.038; ρ = 0.289, p < 0.001). Moreover, β-CTX reached a high value in summer and PINP reached a low value in winter. Conclusion The bone formation markers of female SLE patients without glucocorticoid were lower than those of normal people and the bone resorption marker was higher than that of normal people. The 25 (OH) D of female SLE patients without glucocorticoid was lower than that of normal people. The risk of osteoporosis and fracture may be higher in elderly women with SLE. The bone resorption level of female SLE patients is high in summer and the bone formation level is low in winter.

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SLPI is a critical mediator that controls PTH-induced bone formation

Nature Communications ◽

10.1038/s41467-021-22402-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Akito Morimoto ◽

Junichi Kikuta ◽

Keizo Nishikawa ◽

Takao Sudo ◽

Maki Uenaka ◽

...

Keyword(s):

Parathyroid Hormone ◽

Bone Resorption ◽

Bone Formation ◽

Protease Inhibitor ◽

Bone Metabolism ◽

Serine Protease ◽

Serine Protease Inhibitor ◽

Secretory Leukocyte Protease Inhibitor ◽

Bone Imaging ◽

Genetic Ablation

AbstractOsteoclastic bone resorption and osteoblastic bone formation/replenishment are closely coupled in bone metabolism. Anabolic parathyroid hormone (PTH), which is commonly used for treating osteoporosis, shifts the balance from osteoclastic to osteoblastic, although it is unclear how these cells are coordinately regulated by PTH. Here, we identify a serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), as a critical mediator that is involved in the PTH-mediated shift to the osteoblastic phase. Slpi is highly upregulated in osteoblasts by PTH, while genetic ablation of Slpi severely impairs PTH-induced bone formation. Slpi induction in osteoblasts enhances its differentiation, and increases osteoblast–osteoclast contact, thereby suppressing osteoclastic function. Intravital bone imaging reveals that the PTH-mediated association between osteoblasts and osteoclasts is disrupted in the absence of SLPI. Collectively, these results demonstrate that SLPI regulates the communication between osteoblasts and osteoclasts to promote PTH-induced bone anabolism.

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Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22094717 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4717

Author(s):

Jin-Young Lee ◽

Da-Ae Kim ◽

Eun-Young Kim ◽

Eun-Ju Chang ◽

So-Jeong Park ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Map Kinases ◽

Osteoclast Differentiation ◽

Dependent Manner ◽

Dual Action ◽

Dose Dependent ◽

Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

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