Increased Bone Mass Research Articles

Konjac Oligosaccharides Modulate the Gut Environment and Promote Bone Health in Calcium-Deficient Mice.

This study aimed to investigate the beneficial effect of konjac oligosaccharides (KOS) on bone health in calcium-deficient mice. During the experimental period, low-calcium diet-fed mice were administered with calcium chloride to simulate daily calcium supplementation. Meanwhile, different levels of KOS intervened by adding them into the diet. After 8 weeks, the calcium balance status, bone mass parameters, and gut environment modulation were evaluated. The results showed that dietary KOS intervention alleviated the negative calcium balance, significantly promoted the trabecular number and cortical thickness, and remarkably enhanced the skeletal mechanical strength. Moreover, Pearson's correlation analysis among significantly changed gut microbiota, gut metabolites, and relevant physiological indexes showed that the microbial genera of Lactobacillus, Bifidobacterium, Mucispirillum, Alistipes, and unidentified Clostridia and gut metabolites of kynurenine and testosterone were significantly associated with increased bone mass. These findings provided a new insight into the effect of prebiotics on bone health.

Protective effects of berberine on senile osteoporosis in mice.

The incidence of osteoporosis is positively correlated with age. Berberine has been reported to treat osteoporosis due to its beneficial actions on bone formation. However, the direct effects of berberine on senile osteoporosis remain unclear. The present study investigated the protective effects of berberine on senile osteoporosis in mice and preliminarily evaluated its potential mechanism. 20-month-old male C57BL/6J mice were used as senile osteoporosis mouse model and treated with strontium ranelate (SR) or berberine or solvent control by daily gavage for 2months. Thereafter, bone mass and microstructure parameters were assessed. Histological staining was performed to identify the osteogenic, adipogenic and osteoclastic activity of bone tissue. Moreover, role of cAMP/PKA/CREB signaling pathway in berberine affecting bone marrow mesenchymal stem cells (BMSCs) differentiation was clarified by enzyme-linked immunosorbent assay and western blot analysis. The results showed that the SR-treated group displayed a high trabecular bone mass phenotype. For mice administrated with berberine, cancellous bone mass was upregulated in a dose-dependent manner, as indicated by gradually increased bone mass, trabecular bone volume fraction and trabecular number. Furthermore, berberine promotes osteogenic and inhibits adipogenic differentiation of BMSCs via cAMP/PKA/CREB signaling. Also, bone resorption effect becomes more obvious with increasing dose of berberine in vitro. The present results suggest that berberine exerts potent bone protective effects by promoting bone formation, inhibiting marrow fat accumulation and bone resorption. This effect may be achieved through cAMP/PKA/CREB signaling pathway.

Vitamin D status in pubertal children.

Optimal vitamin D status has a great importance in puberty, which is a period of peak bone mineral acquisition. In this study, we aimed to assess the effect of pubertal period on vitamin D status. The study included totally 200 healthy children, aged between 4 and 14 years. Group 1 included 100 prepubertal, children, aged between 4 and 8 years. Group 2 included 100 pubertal children, aged between 9 and 14 years. They had no chronic illnesses. Ages, heights, weights, genders, Body Mass Indexes (BMIs), socioeconomic and educational status of families were established. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured by high performance liquid chromatography (HPLC). Serum parathyroid hormone (PTH) was evaluated using an immunoradiometric assay kit. Serum calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) levels were measured. We determined that 25(OH)D levels were lower with higher PTH levels in the group aged 9 to 14 years (pubertal children), compared to the group aged 4 to 8 (prepubertal children). Gender, weight, height or BMI, family socioeconomic and education status did not affect serum 25(OH)D levels of children in each group. We demonstrated that vitamin D deficiency was more commonly seen in the pubertal children, compared to pre pubertal period. Children should be supported with vitamin D supplements during the puberty, which has a great importance for rapid increase in bone mass.

Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts.

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.

A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging

Age-related osteoporosis is caused by a deficit in osteoblasts, the cells that secrete bone matrix. The number of osteoblast progenitors also declines with age associated with increased markers of cell senescence. The forkhead box O (FoxO) transcription factors attenuate Wnt/β-catenin signaling and the proliferation of osteoprogenitors, thereby decreasing bone formation. The NAD+-dependent Sirtuin1 (Sirt1) deacetylates FoxOs and β-catenin in osteoblast progenitors and, thereby, increases bone mass. However, it remains unknown whether the Sirt1/FoxO/β-catenin pathway is dysregulated with age in osteoblast progenitors. We found decreased levels of NAD+ in osteoblast progenitor cultures from old mice, associated with increased acetylation of FoxO1 and markers of cell senescence. The NAD+ precursor nicotinamide riboside (NR) abrogated FoxO1 and β-catenin acetylation and several marker of cellular senescence, and increased the osteoblastogenic capacity of cells from old mice. Consistent with these effects, NR administration to C57BL/6 mice counteracted the loss of bone mass with aging. Attenuation of NAD+ levels in osteoprogenitor cultures from young mice inhibited osteoblastogenesis in a FoxO-dependent manner. In addition, mice with decreased NAD+ in cells of the osteoblast lineage lost bone mass at a young age. Together, these findings suggest that the decrease in bone formation with old age is due, at least in part, to a decrease in NAD+ and dysregulated Sirt1/FoxO/β-catenin pathway in osteoblast progenitors. NAD+ repletion, therefore, represents a rational therapeutic approach to skeletal involution.

Cancellous Bone May Have a Greater Adaptive Strain Threshold Than Cortical Bone.

ABSTRACTStrain magnitude has a controlling influence on bone adaptive response. However, questions remain as to how and if cancellous and cortical bone tissues respond differently to varied strain magnitudes, particularly at a molecular level. The goal of this study was to characterize the time‐dependent gene expression, bone formation, and structural response of the cancellous and cortical bone of female C57Bl/6 mice to mechanical loading by applying varying load levels (low: −3.5 N; medium: −5.2 N; high: −7 N) to the skeleton using a mouse tibia loading model. The loading experiment showed that cortical bone mass at the tibial midshaft was significantly enhanced following all load levels examined and bone formation activities were particularly elevated at the medium and high loads applied. In contrast, for the proximal metaphyseal cancellous bone, only the high load led to significant increases in bone mass and bone formation indices. Similarly, expression of genes associated with inhibition of bone formation (e.g., Sost) was altered in the diaphyseal cortical bone at all load levels, but in the metaphyseal cortico‐cancellous bone only by the high load. Finite element analysis determined that the peak tensile or compressive strains that were osteogenic for the proximal cancellous bone under the high load were significantly greater than those that were osteogenic for the midshaft cortical tissues under the low load. These results suggest that the magnitude of the strain stimulus regulating structural, cellular, and molecular responses of bone to loading may be greater for the cancellous tissues than for the cortical tissues. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction

The receptor activator of nuclear factor-kappa B ligand (RANKL) mediates osteoclast differentiation and functions by inducing Ca2+ oscillations, activating mitogen-activated protein kinases (MAPKs), and activating nuclear factor of activated T-cells type c1 (NFATc1) via the RANK and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) interaction. Reactive oxygen species (ROS) also plays an important role during osteoclastogenesis and Sestrin2, an antioxidant, maintains cellular homeostasis upon stress injury via regulation of ROS, autophagy, and inflammation. However, the role of Sestrin2 in osteoclastogenesis remains unknown. In this study, we investigated the role of Sestrin2 in the RANKL-RANK-TRAF6 signaling pathway during osteoclast differentiation. Deletion of Sestrin2 (Sesn2) increased bone mass and reduced the number of multinucleated osteoclasts on bone surfaces. RANKL-induced osteoclast differentiation and function decreased in Sesn2 knockout (KO) bone marrow-derived monocytes/macrophages (BMMs) due to inhibition of NFATc1 expression, but osteoblastogenesis was not affected. mRNA expression of RANKL-induced specific osteoclastogenic genes and MAPK protein expression were lower in Sesn2 KO BMMs than wild-type (WT) BMMs after RANKL treatment. However, the Sesn2 deletion did not affect ROS generation or intracellular Ca2+ oscillations during osteoclastogenesis. In contrast, the interaction between TRAF6 and p62 was reduced during osteoclasts differentiation in Sesn2 KO BMMs. The reduction in the TRAF6/p62 interaction and TRAP activity in osteoclastogenesis in Sesn2 KO BMMs was recovered to the WT level upon expression of Flag-Sesn2 in Sesn2 KO BMMs. These results suggest that Sestrin2 has a novel role in bone homeostasis and osteoclasts differentiation through regulation of NFATc1 and the TRAF6/p62 interaction.

RETRACTED: Effect of resveratrol and mesenchymal stem cell monotherapy and combined treatment in management of osteoporosis in ovariectomized rats: Role of SIRT1/FOXO3a and Wnt/β-catenin pathways

Osteoporosis is a skeletal disorder that is common in postmenopausal women. It is characterized by deteriorated bone mass and microarchitecture. In this study, we aimed to explore the effects and molecular mechanisms of resveratrol and mesenchymal stem cell (MSC) individual and combined treatment in management of osteoporosis in ovariectomized rats. Our results demonstrated that treatment of ovariectomized rats with resveratrol or MSCs improved bone mass and microstructure as indicated by increased bone mineral content and density. Moreover, resveratrol and MSCs stimulated osteogenesis as shown by increased levels of osteogenic markers such as runt-related transcription factor 2 (RUNX2). In addition, resveratrol and MSCs inhibited adipogenesis and osteoclastogenesis as indicated by the suppression of the adipogenic marker, peroxisome proliferator-activated receptor gamma (PPARγ) and the osteoclastogenesis marker, receptor activator of nuclear factor-κB ligand (RANKL). Mechanistically, our results showed that management of osteoporosis in resveratrol or MSC treated rats was achieved by activating two signaling pathways, sirtuin 1 (SIRT1) and wingless-related MMTV integration site (Wnt). Finally, the combination of resveratrol and MSCs was more effective in increasing bone mass and improving osteoporosis than individual treatments.

Maternal vitamin B12 in mice positively regulates bone, but not muscle mass and strength in post-weaning and mature offspring.

Vitamin B12 deficiency has been shown to affect bone mass in rodents and negatively impact bone formation in humans. In this study using mouse models, we define the effect of B12 supplementation in the wild-type mother and B12 deficiency in a mouse genetic model (Gif−/− mice) during gestation on bone and muscle architecture and mechanical properties in the offspring. Analysis of bones from 4-wk-old offspring of the wild-type mother following vehicle or B12 supplementation during gestation (from embryonic day 0.5 to 20.5) showed an increase in bone mass caused by an isolated increase in bone formation in the B12-supplemented group compared with vehicle controls. Analysis of the effect of B12 deficiency in the mother in a mouse genetic model (Gif−/− mice) on the long bone architecture of the offspring showed a compromised cortical and trabecular bone mass, which was completely prevented by a single injection of B12 in the B12-deficient Gif−/− mothers. Biomechanical analysis of long bones of the offspring born from B12-supplemented wild-type mothers showed an increase in bone strength, and conversely, offspring born from B12-deficient Gif−/− mothers revealed a compromised bone strength, which could be rescued by a single injection of B12 in the B12-deficient Gif−/− mother. Muscle structure and function analysis however revealed no significant effect on muscle mass, structure, and grip strength of B12 deficiency or supplementation in Gif−/− mice compared with littermate controls. Together, these results demonstrate the beneficial effect of maternally derived B12 in the regulation of bone structure and function in the offspring.

Theaflavin-3,3'-Digallate Promotes the Formation of Osteoblasts Under Inflammatory Environment and Increases the Bone Mass of Ovariectomized Mice.

Postmenopausal osteoporosis is a disease of bone mass reduction and structural changes due to estrogen deficiency, which can eventually lead to increased pain and fracture risk. Chronic inflammatory microenvironment leading to the decreased activation of osteoblasts and inhibition of bone formation is an important pathological factor that leads to osteoporosis. Theaflavin-3,3′-digallate (TFDG) is an extract of black tea, which has potential anti-inflammatory and antiviral effects. In our study, we found that TFDG significantly increased the bone mass of ovariectomized (OVX) mice by micro-CT analysis. Compared with OVX mice, TFDG reduced the release of proinflammatory cytokines and increased the expression of osteogenic markers in vivo. In vitro experiments demonstrated that TFDG could promote the formation of osteoblasts in inflammatory environment and enhance their mineralization ability. In this process, TFDG activated MAPK, Wnt/β-Catenin and BMP/Smad signaling pathways inhibited by TNF-α, and then promoted the transcription of osteogenic related factors including Runx2 and Osterix, promoting the differentiation and maturation of osteoblasts eventually. In general, our study confirmed that TFDG was able to promote osteoblast differentiation under inflammatory environment, enhance its mineralization ability, and ultimately increase bone mass in ovariectomized mice. These results suggested that TFDG might have the potential to be a more effective treatment of postmenopausal osteoporosis.

Osteogenesis imperfecta in children.

Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility. The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why increased tissue brittleness should be associated with so many other changes is unclear; ER stress, pro-inflammatory cytokines, accelerated senesence and altered matrix component release might all contribute, but a unifying hypothesis remains elusive. New approaches to therapy are focussed on increasing bone mass, following the paradigm established by the treatment of postmenopausal osteoporosis. For adults, this brings the prospect of restoring previously lost bone - for children, particularly at the severe end of the spectrum, the possibility of further reducing fracture frequency and possibly altering growth and long term function are attractive. The alternatives that might affect tissue brittleness are autophagy enhancement (through the removal of abnormal type I collagen aggregates) and stem cell transplantation - both still at the preclinical stage of assessment. Preclinical assessment is not supportive of targeting inflammatory pathways, although understanding why TGFb signalling is increased, and whether that presents a treatment target in OI, remains to be established.

Sclerostin antibody increases trabecular bone and bone mechanical properties by increasing osteoblast activity damaged by whole-body irradiation in mice.

Irradiation therapy causes bone deterioration and increased risk for skeletal-related events. Irradiation interferes with trabecular architecture through increased osteoclastic activity, decreased osteoblastic activity, and increased adipocyte expansion in the bone marrow (BM), which further compounds bone-related disease. Neutralizing antibodies to sclerostin (Scl-Ab) increase bone mass and strength by increasing bone formation and reducing bone resorption. We hypothesized that treatment with Scl-Ab would attenuate the adverse effects of irradiation by increasing bone volume and decreasing BM adipose tissue (BMAT), resulting in better quality bone. In this study, 12-week-old female C57BL/6J mice were exposed to 6Gy whole-body irradiation or were non-irradiated, then administered Scl-Ab (25mg/kg) or vehicle weekly for 5weeks. Femoral μCT analysis confirmed that the overall effect of IR significantly decreased trabecular bone volume/total volume (Tb.BV/TV) (2-way ANOVA, p<0.0001) with a -43.8% loss in Tb.BV/TV in the IR control group. Scl-Ab independently increased Tb.BV/TV by 3.07-fold in non-irradiated and 3.6-fold in irradiated mice (2-way ANOVA, p<0.0001). Irradiation did not affect cortical parameters, although Scl-Ab increased cortical thickness and area significantly in both irradiated and non-irradiated mice (2-way ANOVA, p<0.0001). Femoral mechanical testing confirmed Scl-Ab significantly increased bending rigidity and ultimate moment independently of irradiation (2-way ANOVA, p<0.0001). Static and dynamic histomorphometry of the femoral metaphysis revealed osteoblast vigor, not number, was significantly increased in the irradiated mice treated with Scl-Ab. Systemic alterations were assessed through serum lipidomic analysis, which showed that Scl-Ab normalized lipid profiles in the irradiated group. This data supports the theory of sclerostin as a novel contributor to the regulation of osteoblast activity after irradiation. Overall, our data support the hypothesis that Scl-Ab ameliorates the deleterious effects of whole-body irradiation on bone and adipose tissue in a mouse model. Our findings suggest that future research into localized and systemic therapies after irradiation exposure is warranted.

PPARG in osteocytes controls sclerostin expression, bone mass, marrow adiposity and mediates TZD-induced bone loss.

The peroxisome proliferator activated receptor gamma (PPARG) nuclear receptor regulates energy metabolism and insulin sensitivity. In this study, we present novel evidence for an essential role of PPARG in the regulation of osteocyte function, and support for the emerging concept of the conjunction between regulation of energy metabolism and bone mass. We report that PPARG is essential for sclerostin production, a recently approved target to treat osteoporosis. Our mouse model of osteocyte-specific PPARG deletion (Dmp1CrePparγflfl or γOTKO) is characterized with increased bone mass and reduced bone marrow adiposity, which is consistent with upregulation of WNT signaling and increased bone forming activity of endosteal osteoblasts. An analysis of osteocytes derived from γOTKO and control mice showed an excellent correlation between PPARG and SOST/sclerostin at the transcript and protein levels. The 8kb sequence upstream of Sost gene transcription start site possesses multiple PPARG binding elements (PPREs) with at least two of them binding PPARG with dynamics reflecting its activation with full agonist rosiglitazone and correlating with increased levels of Sost transcript and sclerostin protein expression (Pearson's r=0.991, p=0.001). Older γOTKO female mice are largely protected from TZD-induced bone loss providing proof of concept that PPARG in osteocytes can be pharmacologically targeted. These findings demonstrate that transcriptional activities of PPARG are essential for sclerostin expression in osteocytes and support consideration of targeting PPARG activities with selective modulators to treat osteoporosis.

Chemokine ligand 28 (CCL28) negatively regulates trabecular bone mass by suppressing osteoblast and osteoclast activities.

Bone metabolism imbalances cause bone metabolism diseases, like osteoporosis, through aging. Although some chemokines are known to be involved in bone mass regulation, many have not been investigated. Thus, the present study aimed to investigate the role of chemokine ligand 28 (CCL28) on bone metabolism. To investigate the role of CCL28 on bone metabolism, 10-week-old male wild-type and Ccl28 knockout (Ccl28 KO) mice were analyzed. Microcomputed tomography analysis and bone tissue morphometry were used to investigate the effect of Ccl28 deficiency on the bone. CCL28 localization in bone tissue was assumed by immunohistochemistry. Osteoblast and osteoclast markers were evaluated by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction. Finally, in vitro experiments using MC3T3-E1 and bone marrow macrophages revealed the direct effect of CCL28 on osteoblast and osteoclast. This study showed that Ccl28 deficiency significantly increased bone mass and the number of mature osteoblasts. Immunoreactivity for CCL28 was observed in osteoblasts and osteoclasts on bone tissue. Additionally, Ccl28 deficiency promoted osteoblast and osteoclast maturation. Moreover, CCL28 treatment decreased osteoblast and osteoclast activities but did not affect differentiation. In summary, this study indicated that CCL28 is one of the negative regulators of bone mass by suppressing osteoblast and osteoclast activities. These results provide important insights into bone immunology and the selection of new osteoporosis treatments.

Paleoecological Inferences from Long Bone Microanatomical Specializations in Hippopotamoidea (Mammalia, Artiodactyla)

Hippopotamoids are herbivorous mammals that originated in the late middle Eocene. This taxon includes animals with a great variety of sizes and body proportions, from small and gracile forms with slender limbs to heavy massive ones. Many hippopotamoids have previously been considered semi-aquatic but recent studies have highlighted a diversity of ecologies. This study focuses on bone microanatomy, one of the various proxies that enable inferring the ecology of extinct taxa. The comparative analysis of the inner structure of the stylopod bones in various hippopotamoids, based on both transverse and longitudinal virtual sections, highlights a diversity of patterns and clarifies previously proposed hypotheses about the ecology of the sampled hippopotamoids. The filling of the medullary area by spongious deposits in the pygmy hippopotamus, Choeropsis liberiensis, appears associated with frequent incursions into the water by an animal that essentially forages in forests. The common hippopotamus, Hippopotamus amphibius, which spends most of the day submerged in water, shows a greater filling of the medullary area by spongious bone and a thicker cortex. These observations coupled with comparisons with diverse terrestrial and semi-aquatic mammals of various sizes confirm that semi-aquatic lifestyle and heavy weight-bearing are associated with similar microanatomical specializations causing an increase in bone mass. However, for a given mass, comparisons enable determining if an additional increase in bone compactness occurs, as in Hippopotamus amphibius, in which case a semi-aquatic lifestyle could be inferred. Accordingly, this study suggests an essentially terrestrial lifestyle for Microbunodon minimum, Bothriodon velaunus, Elomeryx borbonicus, Merycopotamus medioximus, Paenanthracotherium bergeri, and probably also Saotherium cf. S. mingoz, a slight degree of water dependence in Brachyodus onoideus, and a stronger one in Libycosaurus bahri and Hexaprotodon garyam, though less intense than in Hippopotamus amphibius. Comparisons with other large terrestrial and semi-aquatic taxa, and based on a large part of the diaphysis, are required to better decipher the microanatomical changes associated with a semi-aquatic lifestyle from those linked to loading in heavy quadrupedal mammals.

Relevant genetic variants are common in women with pregnancy and lactation-associated osteoporosis (PLO) and predispose to more severe clinical manifestations.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare skeletal disorder characterized by early-onset osteoporosis typically manifestating with vertebral compression fractures or transient osteoporosis of the hip. We hypothesized that genetic variants may play a role in the development of PLO. This study aimed to analyze the presence of genetic variants and a potential association with the clinical presentation in PLO. 42 women with PLO were included from 2013 to 2019 in a multicenter study in Germany. All cases underwent comprehensive genetic analysis based on a custom-designed gene panel including genes relevant for skeletal disorders. The skeletal status was assessed using dual-energy X-ray absorptiometry (DXA). Subgroups were further analyzed by serum bone turnover markers (n=31) and high-resolution peripheral computed tomography (HR-pQCT; n=23). We detected relevant genetic variants in 21 women (50%), with LRP5, WNT1 and COL1A1/A2 being the most commonly involved genes. The mean number of vertebral compression fractures was 3.3±3.4 per case with a significantly higher occurrence in the subgroup with genetic variants (4.8±3.7 vs. 1.8±2.3, p=0.02). Among the total cohort, DXA Z-scores were significantly lower at the lumbar spine compared to the femoral neck (p=0.002). HR-pQCT revealed a pronounced reduction of trabecular and cortical thickness, while trabecular number was within the reference range. Eighteen women (43%) received a bone-specific therapy (primarily teriparatide). Overall, a steep increase in bone mass (+37.7%) was observed after 3years. In conclusion, pregnancy and lactation represent skeletal risk factors, which may unmask hereditary bone disorders leading to PLO. These cases were affected more severely. Nevertheless, a timely diagnosis and adequate treatment can ensure a substantial recovery potential even without specific therapy. Patients with genetically induced low bone turnover (e.g.; LRP5, WNT1) may especially benefit from osteo-anabolic medication.

Resveratrol enhances bone formation by modulating inflammation in the mouse periodontitis model.

To evaluate the effect of resveratrol on periodontal bone regeneration after local delivery and to determine its effect on inflammatory mediators. Resveratrol is considered an anti-inflammatory polyphenolic stilbene involved in the modulation of inflammation. Periodontitis was induced in mouse molars using a 5-day ligature model followed by the left second molar extraction and 50µM resveratrol treatment for 1 and 2weeks. We then examined specimens treated for 1week histologically and with immunostaining. Microfocus-computed tomography (micro-CT) was used to examine the bone volume formation. After 1week of treatment, proinflammatory cytokine levels (TNF-alpha and IL6), cells exhibiting neutrophil and macrophage marker (MPO), cell proliferation marker (Ki67), and preosteoblastic marker (RUNX2) reactivity decreased in the resveratrol-treated specimens compared to the control group. In contrast, we observed a higher number of CD31-, F4/80-, and osteocalcin- (OCN-) positive cells in the resveratrol-treated specimens. After 2weeks, micro-CT confirmed an increased bone mass in the region of the extraction socket in the resveratrol-treated group. After 1week, the resveratrol-treated specimens revealed evidence of inflammation modulation compared to the control group. These data suggest that resveratrol not only affects inflammation control but also is useful for treating periodontitis-related tissue defects and bone regeneration.

PTPRJ promotes osteoclast maturation and activity by inhibiting Cbl-mediated ubiquitination of NFATc1 in late osteoclastogenesis.

Bone-resorbing osteoclasts (OCLs) are multinucleated phagocytes, whose central roles in regulating bone formation and homeostasis are critical for normal health and development. OCLs are produced from precursor monocytes in a multistage process that includes initial differentiation, cell-cell fusion, and subsequent functional and morphological maturation; the molecular regulation of osteoclastogenesis is not fully understood. Here, we identify the receptor-type protein tyrosine phosphatase PTPRJ as an essential regulator specifically of OCL maturation. Monocytes from PTPRJ-deficient (JKO) mice differentiate and fuse normally, but their maturation into functional OCLs and their ability to degrade bone are severely inhibited. In agreement, mice lacking PTPRJ throughout their bodies or only in OCLs exhibit increased bone mass due to reduced OCL-mediated bone resorption. We further show that PTPRJ promotes OCL maturation by dephosphorylating the M-CSF receptor (M-CSFR) and Cbl, thus reducing the ubiquitination and degradation of the key osteoclastogenic transcription factor NFATc1. Loss of PTPRJ increases ubiquitination of NFATc1 and reduces its amounts at later stages of osteoclastogenesis, thereby inhibiting OCL maturation. PTPRJ thus fulfills an essential and cell-autonomous role in promoting OCL maturation by balancing between the pro- and anti-osteoclastogenic activities of the M-CSFR and maintaining NFATc1 expression during late osteoclastogenesis.

Static Magnetic Field (2–4 T) Improves Bone Microstructure and Mechanical Properties by Coordinating Osteoblast/Osteoclast Differentiation in Mice

Static magnetic field (SMF), with constant magnetic field strength and direction, has a long history of basic and clinical research in bone biology. Numerous studies demonstrate that exposure to moderate SMF (1 mT-1 T) can increase bone mass and bone density. However, few studies pay attention to the effects of high SMF (>1 T) on the skeletal system. To investigate the physiological effects of high SMF on bone, mice were exposed to 2-4 T SMF for 28 days. Bone microstructure and mechanical properties were examined. The activity of osteoblasts and osteoclasts involved in bone remodeling was evaluated in vivo and in vitro. Compared with the unexposed group, 2-4 T significantly improved the femoral microstructure and tibial mechanical properties. For bone remodeling in vivo, the number of osteoblasts and bone formation was increased, and the osteoclastic number was decreased by 2-4 T. Moreover, the expression of marker proteins in the femur and concentrations of biochemical indicators in serum involved in bone formation were elevated and bone resorption was reduced under 2-4 T SMF. In vitro, osteoblast differentiation was promoted, and the osteoclastic formation and bone resorption ability were inhibited by 2 T SMF. Overall, these results demonstrate that 2-4 T SMF improved bone microarchitecture and strength by stimulating bone formation and restraining bone resorption, and imply that high SMF might become a potential biophysical treatment modality for bone diseases with abnormal bone remodeling. Bioelectromagnetics. © 2021 Bioelectromagnetics Society.

Bone Geometry Is Altered by Follistatin‐Induced Muscle Growth in Young Adult Male Mice

ABSTRACTThe development of the musculoskeletal system and its maintenance depends on the reciprocal relationship between muscle and bone. The size of skeletal muscles and the forces generated during muscle contraction are potent sources of mechanical stress on the developing skeleton, and they shape bone structure during growth. This is particularly evident in hypermuscular global myostatin (Mstn)‐null mice, where larger muscles during development increase bone mass and alter bone shape. However, whether muscle hypertrophy can similarly influence the shape of bones after the embryonic and prepubertal period is unknown. To address this issue, bone structure was assessed after inducing muscle hypertrophy in the lower hindlimbs of young‐adult C57BL/6J male mice by administering intramuscular injections of recombinant adeno‐associated viral vectors expressing follistatin (FST), a potent antagonist of Mstn. Two FST isoforms were used: the full‐length 315 amino acid isoform (FST‐315) and a truncated 288 amino acid isoform (FST‐288). In both FST‐treated cohorts, muscle hypertrophy was observed, and the anterior crest of the tibia, adjacent to the tibialis anterior muscle, was lengthened. Hypertrophy of the muscles surrounding the tibia caused the adjacent cortical shell to recede inward toward the central axis: an event driven by bone resorption adjacent to the hypertrophic muscle. The findings reveal that inducing muscle hypertrophy in mice can confer changes in bone shape in early adulthood. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.