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Muscle and bone interact via physical forces and secreted osteokines and myokines. Physical forces are generated through gravity, locomotion, exercise, and external devices. Cells sense mechanical strain via adhesion molecules and translate it into biochemical responses, modulating the basic mechanisms of cellular biology such as lineage commitment, tissue formation, and maturation. This may result in the initiation of bone formation, muscle hypertrophy, and the enhanced production of extracellular matrix constituents, adhesion molecules, and cytoskeletal elements. Bone and muscle mass, resistance to strain, and the stiffness of matrix, cells, and tissues are enhanced, influencing fracture resistance and muscle power. This propagates a dynamic and continuous reciprocity of physicochemical interaction. Secreted growth and differentiation factors are important effectors of mutual interaction. The acute effects of exercise induce the secretion of exosomes with cargo molecules that are capable of mediating the endocrine effects between muscle, bone, and the organism. Long-term changes induce adaptations of the respective tissue secretome that maintain adequate homeostatic conditions. Lessons from unloading, microgravity, and disuse teach us that gratuitous tissue is removed or reorganized while immobility and inflammation trigger muscle and bone marrow fatty infiltration and propagate degenerative diseases such as sarcopenia and osteoporosis. Ongoing research will certainly find new therapeutic targets for prevention and treatment.

Bone metastases are a frequent and severe complication of advanced-stage cancers. Breast and prostate cancers, the most common malignancies in women and men, respectively, have a particularly high propensity to metastasize to bone. Conceptually, circulating tumour cells (CTCs) in the bloodstream and disseminated tumour cells (DTCs) in the bone marrow provide a snapshot of the dissemination and colonization process en route to clinically apparent bone metastases. Many cell types that constitute the bone microenvironment, including osteoblasts, osteocytes, osteoclasts, adipocytes, endothelial cells, haematopoietic stem cells and immune cells, engage in a dialogue with tumour cells. Some of these cells modify tumour biology, while others are disrupted and out-competed by tumour cells, thus leading to distinct phases of tumour cell migration, dormancy and latency, and therapy resistance and progression to overt bone metastases. Several current bone-protective therapies act by interrupting these interactions, mainly by targeting tumour cell–osteoclast interactions. In this Review, we describe the functional roles of the bone microenvironment and its components in the initiation and propagation of skeletal metastases, outline the biology and clinical relevance of CTCs and DTCs, and discuss established and future therapeutic approaches that specifically target defined components of the bone microenvironment to prevent or treat skeletal metastases.Various cancers can disseminate to the bone, including the most common malignancies in men and women, prostate and breast cancer, respectively. Herein, the authors review the roles of the bone microenvironment in skeletal metastasis, highlighting the biology and clinical relevance of circulating tumour cells and disseminated tumour cells. Notably, bone metastases are associated with considerable morbidity and a poor prognosis, and the authors also discuss established and future therapeutic approaches for targeting components of the bone microenvironment to prevent or treat skeletal metastases.

Background Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all ages. In children HPP-related musculoskeletal symptoms may mimic rheumatologic conditions and diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in the future we studied the natural history of the disease in our large cohort of pediatric patients. This single centre retrospective chart review included longitudinal data from 50 patients with HPP diagnosed and followed at the University Children’s Hospital Wuerzburg, Germany over the last 25 years. Results The cohort comprises 4 (8%) perinatal, 17 (34%) infantile and 29 (58%) childhood onset HPP patients. Two patients were deceased at the time of data collection. Diagnosis was based on available characteristic clinical symptoms (in 88%), low alkaline phosphatase (AP) activity (in 96%), accumulating substrates of AP (in 58%) and X-ray findings (in 48%). Genetic analysis was performed in 48 patients (31 compound heterozygous, 15 heterozygous, 2 homozygous mutations per patient), allowing investigations on genotype-phenotype correlations. Based on anamnestic data, median age at first clinical symptoms was 3.5 months (min. 0, max. 107), while median time to diagnosis was 13 months (min. 0, max. 103). Common symptoms included: impairment of motor skills (78%), impairment of mineralization (72%), premature loss of teeth (64%), musculoskeletal pain and craniosynostosis (each 64%) and failure to thrive (62%). Up to now 20 patients started medical treatment with Asfotase alfa. Conclusions Reported findings support the clinical perception of HPP being a chronic multi-systemic disease with often delayed diagnosis. Our natural history information provides detailed insights into the prevalence of different symptoms, which can help to improve and shorten diagnostics and thereby lead to an optimised medical care, especially with promising therapeutic options such as enzyme-replacement-therapy with Asfotase alfa in mind.

The present study aimed to evaluate the effect of high intensity dynamic resistance exercise (HIT-DRT) and whey protein supplementation (WPS) on bone mineral density (BMD) and sarcopenia parameters in osteosarcopenic men. Men ≥ 72 years with osteosarcopenia (n = 43) were randomly assigned to a HIT-RT (HIT-RT: n = 21) or a non-training control group (n = 22). Supervised HIT-RT twice/week was applied for 18 months, while the control group maintained their habitual lifestyle. Supplying WPS, total protein intake amounted to 1.5–1.6 (HIT-RT) and 1.2 g/kg/body mass/d (control). Both groups were supplied with calcium and vitamin D. Primary study outcomes were BMD and the sarcopenia Z-score. After adjusting for multiplicity, we observed significant positive effects for sarcopenia Z-score (standardized mean difference (SMD): 1.40), BMD at lumbar spine (SMD: 0.72) and total hip (SMD: 0.72). In detail, effect sizes for skeletal muscle mass changes were very pronounced (1.97, p < 0.001), while effects for functional sarcopenia parameters were moderate (0.87, p = 0.008; handgrip strength) or low (0.39, p = 0.209; gait velocity). Apart from one man who reported short periods of temporary worsening of existing joint pain, no HIT-RT/WPS-related adverse effects or injuries were reported. We consider HIT-RT supported by whey protein supplementation as a feasible, attractive, safe and highly effective option to fight osteosarcopenia in older men.

Primary osteoporosis is an age-related disease characterized by an imbalance in bone homeostasis. While the resorptive aspect of the disease has been studied intensely, less is known about the anabolic part of the syndrome or presumptive deficiencies in bone regeneration. Multipotent mesenchymal stem cells (MSC) are the primary source of osteogenic regeneration. In the present study we aimed to unravel whether MSC biology is directly involved in the pathophysiology of the disease and therefore performed microarray analyses of hMSC of elderly patients (79-94 years old) suffering from osteoporosis (hMSC-OP). In comparison to age-matched controls we detected profound changes in the transcriptome in hMSC-OP, e.g. enhanced mRNA expression of known osteoporosis-associated genes (LRP5, RUNX2, COL1A1) and of genes involved in osteoclastogenesis (CSF1, PTH1R), but most notably of genes coding for inhibitors of WNT and BMP signaling, such as Sclerostin and MAB21L2. These candidate genes indicate intrinsic deficiencies in self-renewal and differentiation potential in osteoporotic stem cells. We also compared both hMSC-OP and non-osteoporotic hMSC-old of elderly donors to hMSC of ∼30 years younger donors and found that the transcriptional changes acquired between the sixth and the ninth decade of life differed widely between osteoporotic and non-osteoporotic stem cells. In addition, we compared the osteoporotic transcriptome to long term-cultivated, senescent hMSC and detected some signs for pre-senescence in hMSC-OP.Our results suggest that in primary osteoporosis the transcriptomes of hMSC populations show distinct signatures and little overlap with non-osteoporotic aging, although we detected some hints for senescence-associated changes. While there are remarkable inter-individual variations as expected for polygenetic diseases, we could identify many susceptibility genes for osteoporosis known from genetic studies. We also found new candidates, e.g. MAB21L2, a novel repressor of BMP-induced transcription. Such transcriptional changes may reflect epigenetic changes, which are part of a specific osteoporosis-associated aging process.

Culture medium of mesenchymal stromal cells (MSCs) is usually supplemented with either human platelet lysate (HPL) or fetal calf serum (FCS). Many studies have demonstrated that proliferation and cellular morphology are affected by these supplements – it is therefore important to determine if they favor outgrowth of different subpopulations and thereby impact on the heterogeneous composition of MSCs. We have isolated and expanded human bone marrow-derived MSCs in parallel with HPL or FCS and demonstrated that HPL significantly increases proliferation and leads to dramatic differences in cellular morphology. Remarkably, global DNA-methylation profiles did not reveal any significant differences. Even at the transcriptomic level, there were only moderate changes in pairwise comparison. Furthermore, the effects on proliferation, cytoskeletal organization, and focal adhesions were reversible by interchanging to opposite culture conditions. These results indicate that cultivation of MSCs with HPL or FCS has no systematic bias for specific cell types.

Background Osteosarcopenia is a common geriatric syndrome with an increasing prevalence with age, leading to secondary diseases and complex consequences such as falls and fractures, as well as higher mortality and frailty rates. There is a great need for prevention and treatment strategies. Methods In this analysis, we used magnetic resonance imaging (MRI) data from the randomised controlled FrOST trial, which enrolled community-dwelling osteosarcopenic men aged > 72 years randomly allocated to 16 months of twice-weekly high-intensity resistance training (HIRT) or a non-training control group. MR Dixon imaging was used to quantify the effects of HIRT on muscle fat infiltration in the paraspinal muscles, determined as changes in muscle tissue, fat faction and intermuscular adipose tissue (IMAT) in the erector spinae and psoas major muscles. Intention-to-treat analysis with multiple imputation was used to analyse the data set. Results After 16 months of intervention, 15 men from the HIRT and 16 men from the CG were included in the MRI analysis. In summary, no positive effects on the fat infiltration of the erector spinae and psoas major muscles were observed. Conclusions The previously reported positive effects on lumbar spine bone mineral density (BMD) suggest that mechanotransduction induces tropic effects on bone, but that fat infiltration of the erector spinae and psoas major muscles are either irreversible or, for some unknown reason, resistant to exercise. Because of the beneficial effects on spinal BMD, HIRT is still recommended in osteosarcopenic older men, but further research is needed to confirm appropriate age-specific training exercises for the paraspinal muscles. The potential of different MRI sequences to quantify degenerative and metabolic changes in various muscle groups must be better characterized. Trial registrations FrOST was approved by the University Ethics Committee of the Friedrich-Alexander University of Erlangen-Nürnberg (number 67_15b and 4464b) and the Federal Office for Radiation Projection (BfS, number Z 5–2,246,212 – 2017–002). Furthermore, it fully complies with the Declaration of Helsinki and is registered at ClinicalTrials.gov: NCT03453463 (05/03/2018). JAMA 310:2191–2194, 2013.

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish ( Danio rerio ) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term.

Hypophosphatasia (HPP) is a clinically heterogeneous rare, inherited disorder of bone and mineral metabolism with extensive allelic heterogeneity in the ALPL gene. In this report, we present a family with heterozygous parents (maternal p.(Glu191Lys), paternal p.(Gly334Asp) mutations in the ALPL gene) and four children (one genotypically normal, one heterozygous carrier and two compound heterozygous) showing an unexpected high phenotypic variability. One of the compound heterozygous showed clinical symptoms of the mild childhood form mainly affecting the teeth. The other one was more seriously affected with severe failure to thrive, delayed motor development, need for oxygen supply and profound mineralization deficit compatible with an infantile form of HPP. Functional in vitro studies identified p.(Glu191Lys) as mild (68%, no dominant-negative effect) and p.(Gly334Asp) as severely affected allele (1.2%, dominant-negative effect). In vitro simulation of the children's genetic status showed a residual AP activity of 29%, while the biochemical AP activity in the serum was comparably reduced in both children (22 and 36 U/l). This family report indicates that mapping ALPL mutations within the gene does not necessarily help to predict the clinical severity of the phenotype. Therefore, results of prenatal diagnostics have to be interpreted with caution and prenatal genetic diagnosis and counseling for HPP should be provided within an experienced multidisciplinary team. Research about other confounding factors is urgently needed.