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In vitro co-cultures of different primary human cell types are pivotal for the testing and evaluation of biomaterials under conditions that are closer to the human in vivo situation. Especially co-cultures of macrophages and mesenchymal stem cells (MSCs) are of interest, as they are both present and involved in tissue regeneration and inflammatory reactions and play crucial roles in the immediate inflammatory reactions and the onset of regenerative processes, thus reflecting the decisive early phase of biomaterial contact with the host. A co-culture system of these cell types might thus allow for the assessment of the biocompatibility of biomaterials. The establishment of such a co-culture is challenging due to the different in vitro cell culture conditions. For human macrophages, medium is usually supplemented with human serum (hS), whereas hMSC culture is mostly performed using fetal calf serum (FCS), and these conditions are disadvantageous for the respective other cell type. We demonstrate that human platelet lysate (hPL) can replace hS in macrophage cultivation and appears to be the best option for co-cultivation of human macrophages with hMSCs. In contrast to FCS and hS, hPL maintained the phenotype of both cell types, comparable to that of their respective standard culture serum, as well as the percentage of each cell population. Moreover, the expression profile and phagocytosis activity of macrophages was similar to hS.
Aseptic loosening of total hip and knee joint replacements is the most common indication for revision surgery after primary hip and knee arthroplasty. Research suggests that exposure and uptake of wear by mesenchymal stromal cells (MSC) and macrophages results in the secretion of proinflammatory cytokines and local osteolysis, but also impaired cell viability and regenerative capacity of MSC. Therefore, this in vitro study compared the regenerative and differentiation capacity of MSC derived from patients undergoing primary total hip arthroplasty (MSCprim) to MSC derived from patients undergoing revision surgery after aseptic loosening of total hip and knee joint implants (MSCrev). Regenerative capacity was examined by measuring the cumulative population doubling (CPD) in addition to the number of passages until cells stopped proliferating. Osteogenesis and adipogenesis in monolayer cultures were assessed using histological stainings. Furthermore, RT‐PCR was performed to evaluate the relative expression of osteogenic and adipogenic marker genes as well as the expression of markers for a senescence‐associated secretory phenotype (SASP). MSCrev possessed a limited regenerative capacity in comparison to MSCprim. Interestingly, MSCrev also showed an impaired osteogenic and adipogenic differentiation capacity compared to MSCprim and displayed a SASP early after isolation. Whether this is the cause or the consequence of the aseptic loosening of total joint implants remains unclear. Future research should focus on the identification of specific cell markers on MSCprim, which may influence complication rates such as aseptic loosening of total joint arthroplasty to further individualize and optimize total joint arthroplasty.
In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/β-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice.
The signal modelling framework JimenaE simulates dynamically Boolean networks. In contrast to SQUAD, there is systematic and not just heuristic calculation of all system states. These specific features are not present in CellNetAnalyzer and BoolNet. JimenaE is an expert extension of Jimena, with new optimized code, network conversion into different formats, rapid convergence both for system state calculation as well as for all three network centralities. It allows higher accuracy in determining network states and allows to dissect networks and identification of network control type and amount for each protein with high accuracy. Biological examples demonstrate this: (i) High plasticity of mesenchymal stromal cells for differentiation into chondrocytes, osteoblasts and adipocytes and differentiation-specific network control focusses on wnt-, TGF-beta and PPAR-gamma signaling. JimenaE allows to study individual proteins, removal or adding interactions (or autocrine loops) and accurately quantifies effects as well as number of system states. (ii) Dynamical modelling of cell–cell interactions of plant Arapidopsis thaliana against Pseudomonas syringae DC3000: We analyze for the first time the pathogen perspective and its interaction with the host. We next provide a detailed analysis on how plant hormonal regulation stimulates specific proteins and who and which protein has which type and amount of network control including a detailed heatmap of the A.thaliana response distinguishing between two states of the immune response. (iii) In an immune response network of dendritic cells confronted with Aspergillus fumigatus, JimenaE calculates now accurately the specific values for centralities and protein-specific network control including chemokine and pattern recognition receptors.
Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water‐equivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non‐inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off‐label to treat BML. A randomized, triple‐blind, placebo‐controlled phase III trial was conducted to assess efficacy and safety of single‐dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53% (±41.92%) in patients receiving zoledronic acid and increased by 14.43% (±150.46%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5% of patients receiving ZOL and in 50% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow‐up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single‐dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only.
In contrast to postmenopausal women, evidence for a favorable effect of exercise on Bone Mineral Density (BMD) is still limited for men. This might be due to the paucity of studies, but also to the great variety of participants and study characteristics that may dilute study results. The aim of the present systematic review and meta-analysis was to evaluate the effect of exercise on BMD changes with rational eligibility criteria. A comprehensive search of six electronic databases up to 15 March 2021 was conducted. Briefly, controlled trials ≥6 months that determined changes in areal BMD in men >18 years old, with no apparent diseases or pharmacological therapy that relevantly affect bone metabolism, were included. BMD changes (standardized mean differences: SMD) of the lumbar spine (LS) and femoral neck (FN) were considered as outcomes. Twelve studies with 16 exercise and 12 control groups were identified. The pooled estimate of random-effect analysis was SMD = 0.38, 95%-CI: 0.14–0.61 and SMD = 0.25, 95%-CI: 0.00–0.49, for LS and FN, respectively. Heterogeneity between the trials was low–moderate. Funnel plots and rank and regression correlation tests indicate evidence for small study publication bias for LS but not FN-BMD. Subgroup analyses that focus on study length, type of exercise and methodologic quality revealed no significant difference between each of the three categories. In summary, we provided further evidence for a low but significant effect of exercise on BMD in men. However, we are currently unable to give even rough exercise recommendations for male cohorts.
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.
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.
Metabolic glycoengineering enables a directed modification of cell surfaces by introducing target molecules to surface proteins displaying new features. Biochemical pathways involving glycans differ in dependence on the cell type; therefore, this technique should be tailored for the best results. We characterized metabolic glycoengineering in telomerase-immortalized human mesenchymal stromal cells (hMSC-TERT) as a model for primary hMSC, to investigate its applicability in TERT-modified cell lines. The metabolic incorporation of N-azidoacetylmannosamine (Ac\(_4\)ManNAz) and N-alkyneacetylmannosamine (Ac\(_4\)ManNAl) into the glycocalyx as a first step in the glycoengineering process revealed no adverse effects on cell viability or gene expression, and the in vitro multipotency (osteogenic and adipogenic differentiation potential) was maintained under these adapted culture conditions. In the second step, glycoengineered cells were modified with fluorescent dyes using Cu-mediated click chemistry. In these analyses, the two mannose derivatives showed superior incorporation efficiencies compared to glucose and galactose isomers. In time-dependent experiments, the incorporation of Ac\(_4\)ManNAz was detectable for up to six days while Ac\(_4\)ManNAl-derived metabolites were absent after two days. Taken together, these findings demonstrate the successful metabolic glycoengineering of immortalized hMSC resulting in transient cell surface modifications, and thus present a useful model to address different scientific questions regarding glycosylation processes in skeletal precursors.