Analysis of the human endogenous coregulator complexome.

Elucidation of endogenous cellular protein-protein interactions and their networks is most desirable for biological studies. Here we report our study of endogenous human coregulator protein complex networks obtained from integrative mass spectrometry-based analysis of 3290 affinity purifications. By preserving weak protein interactions during complex isolation and utilizing high levels of reciprocity in the large dataset, we identified many unreported protein associations, such as a transcriptional network formed by ZMYND8, ZNF687, and ZNF592. Furthermore, our work revealed a tiered interplay within networks that share common proteins, providing a conceptual organization of a cellular proteome composed of minimal endogenous modules (MEMOs), complex isoforms (uniCOREs), and regulatory complex-complex interaction networks (CCIs). This resource will effectively fill a void in linking correlative genomic studies with an understanding of transcriptional regulatory protein functions within the proteome for formulation and testing of future hypotheses.

Adrenalectomy Improves Body Weight, Glucose, and Blood Pressure Control in Patients With Mild Autonomous Cortisol Secretion: Results of an Randomized Controlled Trial by the Co-work of Adrenal Research (COAR) Study.

OBJECTIVE: To assess the metabolic effects of adrenalectomy in patients with mild autonomous cortisol secretion (MACS). BACKGROUND: Despite retrospective studies showing the association of adrenalectomy for MACS with beneficial metabolic effects, there have been only 2 randomized prospective studies with some limitations to date. METHODS: A prospective, multicenter study randomized 132 patients with adrenal incidentaloma without any features of Cushing syndrome but with serum cortisol >50 nmol/L after a 1 mg overnight dexamethasone suppression test into an adrenalectomy group (n = 66) or control group (n = 66). The primary outcomes were changes in body weight, glucose, and blood pressure (BP). RESULTS: Among the 118 participants who completed the study with a median follow-up duration of 48 months (range: 3-66), the adrenalectomy group (n = 46) exhibited a significantly higher frequency of improved weight control, glucose control, and BP control (32.6%, 45.7%, and 45.7%, respectively) compared with the control group (n = 46; 6.5%, P = 0.002; 15.2%, P = 0.002; and 23.9%, P = 0.029, respectively) after matching for age and sex. Adrenalectomy [odds ratio (OR) = 10.38, 95% CI = 2.09-51.52, P = 0.004], body mass index (OR = 1.39, 95% CI = 1.08-1.79, P = 0.010), and cortisol after a 1 mg overnight dexamethasone suppression test levels (OR = 92.21, 95% CI = 5.30-1604.07, P = 0.002) were identified as independent factors associated with improved weight control. Adrenalectomy (OR = 5.30, 95% CI = 1.63-17.25, P = 0.006) and diabetes (OR = 8.05, 95% CI = 2.34-27.65, P = 0.001) were independently associated with improved glucose control. Adrenalectomy (OR = 2.27, 95% CI = 0.87-5.94, P = 0.095) and hypertension (OR = 10.77, 95% CI = 3.65-31.81, P < 0.001) demonstrated associations with improved BP control. CONCLUSIONS: adrenalectomy improved weight, glucose, and BP control in patients with MACS.

Ultrathin Serpentine Insulation Layer Architecture for Ultralow Power Gas Sensor.

Toxic gases have surreptitiously influenced the health and environment of contemporary society with their odorless/colorless characteristics. As a result, a pressing need for reliable and portable gas-sensing devices has continuously increased. However, with their negligence to efficiently microstructure their bulky supportive layer on which the sensing and heating materials are located, previous semiconductor metal-oxide gas sensors have been unable to fully enhance their power efficiency, a critical factor in power-stringent portable devices. Herein, an ultrathin insulation layer with a unique serpentine architecture is proposed for the development of a power-efficient gas sensor, consuming only 2.3 mW with an operating temperature of 300 °C (≈6% of the leading commercial product). Utilizing a mechanically robust serpentine design, this work presents a fully suspended standalone device with a supportive layer thickness of only ≈50 nm. The developed gas sensor shows excellent mechanical durability, operating over 10 000 on/off cycles and ≈2 years of life expectancy under continuous operation. The gas sensor detected carbon monoxide concentrations from 30 to 1 ppm with an average response time of ≈15 s and distinguishable sensitivity to 1 ppm (ΔR/R0 = 5%). The mass-producible fabrication and heating efficiency presented here provide an exemplary platform for diverse power-efficient-related devices.

Kinase inhibitor pulldown assay (KiP) for clinical proteomics.

Protein kinases are frequently dysregulated and/or mutated in cancer and represent essential targets for therapy. Accurate quantification is essential. For breast cancer treatment, the identification and quantification of the protein kinase ERBB2 is critical for therapeutic decisions. While immunohistochemistry (IHC) is the current clinical diagnostic approach, it is only semiquantitative. Mass spectrometry-based proteomics offers quantitative assays that, unlike IHC, can be used to accurately evaluate hundreds of kinases simultaneously. The enrichment of less abundant kinase targets for quantification, along with depletion of interfering proteins, improves sensitivity and thus promotes more effective downstream analyses. Multiple kinase inhibitors were therefore deployed as a capture matrix for kinase inhibitor pulldown (KiP) assays designed to profile the human protein kinome as broadly as possible. Optimized assays were initially evaluated in 16 patient derived xenograft models (PDX) where KiP identified multiple differentially expressed and biologically relevant kinases. From these analyses, an optimized single-shot parallel reaction monitoring (PRM) method was developed to improve quantitative fidelity. The PRM KiP approach was then reapplied to low quantities of proteins typical of yields from core needle biopsies of human cancers. The initial prototype targeting 100 kinases recapitulated intrinsic subtyping of PDX models obtained from comprehensive proteomic and transcriptomic profiling. Luminal and HER2 enriched OCT-frozen patient biopsies subsequently analyzed through KiP-PRM also clustered by subtype. Finally, stable isotope labeled peptide standards were developed to define a prototype clinical method. Data are available via ProteomeXchange with identifiers PXD044655 and PXD046169.

Aortic carboxypeptidase-like protein, a putative myokine, stimulates the differentiation and survival of bone-forming osteoblasts.

A new target that stimulates bone formation is needed to overcome limitations of current anti-osteoporotic drugs. Myokines, factors secreted from muscles, may modulate it. In this study, we investigated the role of aortic carboxypeptidase-like protein (ACLP), which is highly expressed in skeletal muscles, on bone formation. MC3T3-E1 cells and/or calvaria osteoblasts were treated with recombinant N-terminal mouse ACLP containing a signal peptide [rmACLP (N)]. The expression and secretion of ACLP were higher in skeletal muscle and differentiated myotube than in other tissues and undifferentiated myoblasts, respectively. rmACLP (N) increased bone formation, ALP activity, and phosphorylated p38 mitogen-activated protein (MAP) kinase in osteoblasts; reversal was achieved by pre-treatment with a TGF-ß receptor inhibitor. Under H2 O2 treatment, rmACLP (N) increased osteoblast survival, phosphorylated p38 MAP kinase, and the nuclear translocation of FoxO3a in osteoblasts. H2 O2 treatment caused rmACLP (N) to suppress its apoptotic, oxidative, and caspase-9 activities. rmACLP (N)-stimulated osteoblast survival was reversed by pre-treatment with a p38 inhibitor, a TGF-ß-receptor II blocking antibody, and a FoxO3a shRNA. Conditioned media (CM) from muscle cells stimulated osteoblast survival under H2 O2 treatment, in contrast to CM from ACLP knockdown muscle cells. rmACLP (N) increased the expressions of FoxO3a target anti-oxidant genes such as Sod2, Trx2, and Prx5. In conclusion, ACLP stimulated the differentiation and survival of osteoblasts. This led to the stimulation of bone formation by the activation of p38 MAP kinase and/or FoxO3a via TGF-ß receptors. These findings suggest a novel role for ACLP in bone metabolism as a putative myokine.

Vacancies in growing habitats promote the evolution of cooperation.

We study evolutionary game dynamics in a growing habitat with vacancies. Fitness is determined by the global effect of the environment and a local prisoner's dilemma among neighbors. We study population growth on a one-dimensional lattice and analyze how the environment affects evolutionary competition. As the environment becomes harsh, an absorbing phase transition from growing populations to extinction occurs. The transition point depends on which strategies are present in the population. In particular, we find a 'cooperative window' in parameter space, where only cooperators can survive. A mutant defector in a cooperative community might briefly proliferate, but over time naturally occurring vacancies separate cooperators from defectors, thereby driving defectors to extinction. Our model reveals that vacancies provide a strong boost for cooperation by spatial selection.

High Risk of Fractures Within 7 Years of Diagnosis in Asian Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: In this nationwide population-based study, we investigated the risk of vertebral and hip fractures in patients with inflammatory bowel disease (IBD). METHODS: Using data from the Korean National Health Insurance claims database gathered between 2007 and 2016, we calculated the incidence rate ratios (IRRs) of vertebral and hip fractures in patients with newly diagnosed IBD (n = 18,228; 64.1% male, 65.9% ulcerative colitis) compared with an age- and sex-matched control population (matching ratio, 1:10; n = 186,871). RESULTS: During a median follow-up period of 4.5 years, the incidence rate and IRR of vertebral and hip fractures in patients with IBD were 2.88 per 1000 person-years and 1.24 (95% CI, 1.08-1.42), respectively. The cumulative risk of vertebral and hip fractures in IBD patients was 0.6%, 1.4%, and 1.9% at 2, 5, and 7 years after diagnosis, respectively, and this risk of fracture in IBD patients was higher than that in matched controls (P = .002). The use of corticosteroids further increased the risk of fractures in IBD patients (IRR, 1.37; 95% CI, 1.13-1.65) compared with matched controls. The risk of fractures was significantly higher in patients with Crohn's disease (CD) (IRR, 1.56; 95% CI, 1.19-2.04) than in matched controls, and this risk remained higher in patients with CD without corticosteroid exposure (IRR, 1.62; 95% CI, 1.12-2.34). The risk of fracture increased with age and was particularly high in females and in those with comorbidities. CONCLUSIONS: The risk of fractures was significantly high in newly diagnosed IBD patients, especially in those with CD regardless of corticosteroid exposure.

RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer.

BACKGROUND: Oestrogen Receptor 1 (ESR1) mutations are frequently acquired in oestrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who were treated with aromatase inhibitors (AI) in the metastatic setting. Acquired ESR1 mutations are associated with poor prognosis and there is a lack of effective therapies that selectively target these cancers. METHODS: We performed a proteomic kinome analysis in ESR1 Y537S mutant cells to identify hyperactivated kinases in ESR1 mutant cells. We validated Recepteur d'Origine Nantais (RON) and PI3K hyperactivity through phospho-immunoblot analysis, organoid growth assays, and in an in vivo patient-derived xenograft (PDX) metastatic model. RESULTS: We demonstrated that RON was hyperactivated in ESR1 mutant models, and in acquired palbociclib-resistant (PalbR) models. RON and insulin-like growth factor 1 receptor (IGF-1R) interacted as shown through pharmacological and genetic inhibition and were regulated by the mutant ER as demonstrated by reduced phospho-protein expression with endocrine therapies (ET). We show that ET in combination with a RON inhibitor (RONi) decreased ex vivo organoid growth of ESR1 mutant models, and as a monotherapy in PalbR models, demonstrating its therapeutic efficacy. Significantly, ET in combination with the RONi reduced metastasis of an ESR1 Y537S mutant PDX model. CONCLUSIONS: Our results demonstrate that RON/PI3K pathway inhibition may be an effective treatment strategy in ESR1 mutant and PalbR MBC patients. Clinically our data predict that ET resistance mechanisms can also contribute to CDK4/6 inhibitor resistance.

Serum GDF15 Level Is Independent of Sarcopenia in Older Asian Adults.

BACKGROUND: Growth differentiation factor 15 (GDF15), induced by tissue inflammation and mitochondrial stress, has received significant attention as a biomarker of mitochondrial dysfunction and has been implicated in various age-related diseases. However, the association between circulating GDF15 and sarcopenia-associated outcomes in older adults remains to be established. AIM: To validate previous experimental data and to investigate the possible role of GDF15 in aging and muscle physiology in humans, this study examined serum GDF15 levels in relation to sarcopenia-related parameters in a cohort of older Asian adults. METHODS: Muscle mass and muscle function-related parameters, such as grip strength, gait speed, chair stands, and short physical performance battery score were evaluated by experienced nurses in 125 geriatric participants with or without sarcopenia. Sarcopenia was diagnosed using the Asian-specific cutoff points. Serum GDF15 levels were measured using an enzyme immunoassay kit. RESULTS: Serum GDF15 levels were not significantly different according to sarcopenia status, muscle mass, muscle strength, and physical performance and were not associated with the skeletal muscle index, grip strength, gait speed, time to complete 5 chair stands, and short physical performance battery score, regardless of adjustments for sex, age, and BMI. CONCLUSIONS: These findings indicate that the definite role of GDF15 on muscle metabolism observed in animal models might not be evident in humans and that elevated GDF15 levels might not predict the risk for sarcopenia, at least in older Asian adults.

DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer.

A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive ([Formula: see text]) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative ([Formula: see text]) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.

Power-grid stability predictions using transferable machine learning.

Complex network analyses have provided clues to improve power-grid stability with the help of numerical models. The high computational cost of numerical simulations, however, has inhibited the approach, especially when it deals with the dynamic properties of power grids such as frequency synchronization. In this study, we investigate machine learning techniques to estimate the stability of power-grid synchronization. We test three different machine learning algorithms-random forest, support vector machine, and artificial neural network-training them with two different types of synthetic power grids consisting of homogeneous and heterogeneous input-power distribution, respectively. We find that the three machine learning models better predict the synchronization stability of power-grid nodes when they are trained with the heterogeneous input-power distribution rather than the homogeneous one. With the real-world power grids of Great Britain, Spain, France, and Germany, we also demonstrate that the machine learning algorithms trained on synthetic power grids are transferable to the stability prediction of the real-world power grids, which implies the prospective applicability of machine learning techniques on power-grid studies.

Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt 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.

Increased Expression of 11ß-Hydroxysteroid Dehydrogenase Type 1 Contributes to Epidermal Permeability Barrier Dysfunction in Aged Skin.

Inactive cortisone is converted into active cortisol by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). Excessive levels of active glucocorticoids could deteriorate skin barrier function; barrier impairment is also observed in aged skin. In this study, we aimed to determine whether permeability barrier impairment in the aged skin could be related to increased 11ß-HSD1 expression. Aged humans (n = 10) showed increased cortisol in the stratum corneum (SC) and oral epithelium, compared to young subjects (n = 10). 11ß-HSD1 expression (as assessed via immunohistochemical staining) was higher in the aged murine skin. Aged hairless mice (56-week-old, n = 5) manifested greater transepidermal water loss, lower SC hydration, and higher levels of serum inflammatory cytokines than the young mice (8-week-old, n = 5). Aged 11ß-HSD1 knockout mice (n = 11), 11ß-HSD1 inhibitor (INHI)-treated aged wild type (WT) mice (n = 5) and young WT mice (n = 10) exhibited reduced SC corticosterone level. Corneodesmosome density was low in WT aged mice (n = 5), but high in aged 11ß-HSD1 knockout and aged INHI-treated WT mice. Aged mice exhibited lower SC lipid levels; this effect was reversed by INHI treatment. Therefore, upregulation of 11ß-HSD1 in the aged skin increases the active-glucocorticoid levels; this suppresses SC lipid biosynthesis, leading to impaired epidermal permeability barrier.

Surgical Correction of Upper Eyelid Ectropion Presenting Dry Eye Symptoms.

BACKGROUND: Upper eyelid ectropion occurs as a post-blepharoplasty complication or involution change, and it causes dry eye symptoms that cannot be resolved with conservative management. OBJECTIVES: The aim of this study is to describe the authors' surgical technique of anatomical correction of upper eyelid ectropion, including tarsal scoring incision. METHODS: The technique involves the following 4 steps: (1) adhesiolysis at the preaponeurotic layer; (2) undermining and redraping of the pretarsal flap in a pretarsal plane; (3) optional, partial thickness tarsal scoring incision over the central two-thirds; and (4) downward repositioning of the pretarsal flap and lower fixation to the tarsus. Outcomes were assessed based on the position of eyelid margin and the improvement of the dry eye symptoms. RESULTS: A retrospective review of 54 cases of patients who underwent ectropion correction, including tarsal scoring incision, was performed. The eyelid margin was well positioned in 51 patients (94.4%). Of the 32 patients involved in the study assessed with the 7-point Patient Global Impression of Improvement, 29 (90.6%) reported the resolution of dry eye symptoms. Furthermore, in the 22 patients assessed with the Ocular Surface Disease Index, the mean score significantly decreased from 43.2 ±â€…24.1 before surgery to 29.8 ±â€…23.3 (P = 0.006) after surgery. CONCLUSIONS: The combination of partial-thickness tarsal plate scoring and lower flap redraping surgical techniques resolved the upper eyelid ectropion, reducing the dry eye symptoms.

Coupling factors involved in preserving bone balance.

Coupling during bone remodeling refers to the spatial and temporal coordination of bone resorption with bone formation. Studies have assessed the subtle interactions between osteoclasts and osteoblasts to preserve bone balance. Traditionally, coupling research related to osteoclast function has focused on bone resorption activity causing the release of growth factors embedded in the bone matrix. However, considerable evidence from in vitro, animal, and human studies indicates the importance of the osteoclasts themselves in coupling phenomena, and many osteoclast-derived coupling factors have been identified. These include sphingosine-1-phosphate, vesicular-receptor activator of nuclear factor-κB, collagen triple helix repeat containing 1, and cardiotrophin-1. Interestingly, neuronal guidance molecules, such as slit guidance ligand 3, semaphorin (SEMA) 3A, SEMA4D, and netrin-1, originally identified as instructive cues allowing the navigation of growing axons to their targets, have been shown to be involved in the intercellular cross-talk among bone cells. This review discusses osteoclast-osteoblast coupling signals, including recent advances and the potential roles of these signals as therapeutic targets for osteoporosis and as biomarkers predicting human bone health.

Lack of association between circulating apelin level and frailty-related functional parameters in older adults: a cross-sectional study.

BACKGROUND: Apelin, an active endogenous peptide, has been recently receiving great attention as a promising target for antiaging intervention, primarily based on results from genetically altered mice. To validate previous experimental data and investigate the possible role of apelin in humans, in this study, we examined serum apelin level in relation to frailty and its associated parameters in a cohort of ambulatory, community-dwelling older adults. METHODS: Blood samples were collected from 80 participants who underwent a comprehensive geriatric assessment, and apelin level was measured using an enzyme immunoassay kit. Phenotypic frailty and deficit-accumulation frailty index (FI) were assessed using widely validated approaches, proposed by Fried and Rockwood groups, respectively. RESULTS: After adjustment for sex, age, and body mass index, serum apelin level was found to be not significantly different according to phenotypic frailty status (P = 0.550) and not associated with FI, grip strength, gait speed, time to complete 5 chair stands, and muscle mass (P = 0.433 to 0.982). To determine whether the association between serum apelin level and frailty has a threshold effect, we divided the participants into quartiles according to serum apelin level. However, there were no differences in terms of frailty-related parameters and the risk for frailty among the quartile groups (P = 0.248 to 0.741). CONCLUSIONS: The serum apelin level was not associated with both phenotypic frailty and functional parameters in older adults, despite its beneficial effects against age-related physiologic decline in animal models. Further large-scale longitudinal studies are necessary to understand the definite role of circulating apelin in frailty risk assessment.

Immediate Reconstruction of Amputated Ear With Fascia Flap.

BACKGROUND: Various surgical methods have been used for reconstruction of an amputated ear, including microsurgical replantation and delayed reconstruction using synthetic material or autologous rib cartilage. The authors share our experience of immediate reconstruction using amputated cartilage and discuss the advantages compared to other techniques of reconstruction. MATERIALS AND METHODS: The authors retrospectively reviewed the medical records of 3 patients who underwent immediate reconstruction of amputated ear by a single operator. In the cases, the amputees were washed; the skin and cartilage were separated. The ear cartilage was fixed to its original position with non-absorbable suture. Regional fascia flap was elevated and covered the ear cartilage. The amputee skin was redraped to cover the fascia flap. Several months after the operation, photographic assessment was done. RESULTS: All 3 cases showed well-defined convolution, tolerable skin color, and patient satisfaction without any major complications. A patient showed mild temporal incision site alopecia. CONCLUSION: The above immediate reconstruction method can achieve reliable and favorable result with minimal complications.

SLIT2 inhibits osteoclastogenesis and bone resorption by suppression of Cdc42 activity.

Axon guidance molecules, originally found to mediate the positioning of axons during nerve development, have been receiving great attention due to their critical roles in regulating bone metabolism. Recently, SLITs, another group of neuronal guidance proteins, were found to be significantly expressed in bone cells. Furthermore, we had provided experimental evidence that SLIT3 is an osteoclast-secreted coupling factor playing an osteoprotective role. Therefore, we hypothesized that SLIT2, a member of the SLIT family, may also affect bone homeostasis. SLIT2 suppressed osteoclast differentiation in a dose-dependent manner and in vitro bone resorption by more than 80%. Consistently, the expression of osteoclast differentiation markers, such as tartrate-resistant acid phosphatase (Trap) and calcitonin receptor (Ctr), was decreased by SLIT2. The migration and fusion of preosteoclasts were markedly reduced in the presence of SLIT2, suggesting that SLIT2 mainly functions in the early stage of osteoclastogenesis. SLIT2 suppressed Cdc42 activity among small GTPases, whereas Cdc42 overexpression almost completely reversed the SLIT2-mediated suppression of osteoclast differentiation. Among ROBO1-4, the SLIT receptors, ROBO1 and ROBO3 were known to be predominantly expressed in osteoclast lineages. A binding ELISA experiment in mouse bone marrow-derived macrophages showed that ROBO1, rather than ROBO3, was directly associated with SLIT2, and gene silencing with Robo1 siRNA blocked the SLIT2-mediated suppression of osteoclastogenesis. Taken together, our results indicated that SLIT2 inhibits osteoclastogenesis and the resultant bone resorption by decreasing Cdc42 activity, suggesting that this was a potential therapeutic target in metabolic bone diseases related to high bone turnover states.

The effects of myokines on osteoclasts and osteoblasts.

Recently, muscle has received much attention as an endocrine organ regulating other biological targets, including the pancreas, liver, and adipose tissue. Although there is a possibility that muscle-secreting factors biochemically affect bone metabolism in a paracrine manner, the net effects of myokines on the biology of osteoclasts and osteoblasts, particularly on bone mass in vivo, have not yet been thoroughly investigated. Therefore, we performed in vitro as well as animal experiments using conditioned media (CM) collected from C2C12 myoblast and myotube cultures to better understand the interactions between muscle and bone. Compared with non-CM (i.e., control) and myoblast CM, myotube CM markedly inhibited in vitro bone resorption through the suppression of osteoclast differentiation and resorptive activity of individual osteoclasts. Consistently, the expressions of osteoclast differentiation markers, such as tartrate-resistant acid phosphatase (Trap) and calcitonin receptor (Ctr), decreased with myotube CM. Myotube CM significantly stimulated preosteoblast viability and migration and reduced apoptosis, thereby resulting in an increase in calvaria bone formation. Importantly, systemic treatment with myotube CM for 4 weeks increased bone per tissue volume by 30.7% and 19.6% compared with control and myoblast CM, respectively. These results support the hypothesis that muscle plays beneficial roles in bone health via secretion of anabolic factors, in addition to mechanical stimuli, and importantly indicate that muscle-derived factors can be potential therapeutic targets against metabolic bone diseases.

Lack of Association Between Vitamin D and Hand Grip Strength in Asians: A Nationwide Population-Based Study.

Despite the beneficial role and plausible mechanism of vitamin D on skeletal muscle in animal studies, its association in humans remains a controversial issue due to inconsistent clinical results, especially in older Asians. This was a population-based, cross-sectional study from the Korea National Health and Nutrition Examination Surveys, which enrolled 354 men aged ≥ 50 years and 328 postmenopausal women. Hand grip strength (HGS) was measured using a digital grip strength dynamometer. Low muscle strength was defined based on Korean-specific cut-off point of HGS. Serum 25-hydroxyvitamin D [25(OH)D] levels were 19.4 ± 6.7 and 17.1 ± 7.2 ng/mL in men and women, respectively. Among covariates including age, body mass index, lifestyle factors, and protein intake, age was inversely associated with HGS in both men and women, and protein intake (g/day) was positively associated with HGS only in men. However, the independent correlation between serum 25(OH)D and HGS was not observed, regardless of gender. When subjects were divided into three groups [deficient (25(OH)D < 20 ng/mL; 63.8%), insufficient (20 ≤ 25(OH)D < 30 ng/mL; 30.0%), or sufficient (25(OH)D ≥ 30 ng/mL; 6.2%)], there was no significant difference in HGS among these groups in both men and women. Consistently, serum 25(OH)D was not significantly different between subjects with and without low muscle strength, and there was no independent association of serum 25(OH)D with the risk of low muscle strength in both genders. These findings provide clinical evidence that protective role of vitamin D on human muscle metabolism may not be evident at least in older Asians.