Biology subjects

Schulte, F. A.

Publications and source records attributed to Schulte, F. A..

6 recordsLinked to original sources

bioRxiv2026

Dysregulated mechanoregulation of load-induced bone adaptation in prematurely aged mice: insights from a micro-multiphysics agent-based model

Bone exhibits remarkable ability to adapt to varying mechanical demands. Aging can lead to changes in distribution of cells and proteins that directly affect bone formation and resorption. Given the inherent challenges of quantifying these cellular and protein alterations in vivo, innovative in silico tools have proven useful to contribute to studying the impact of aging on bone mechanobiology and associated cellular mechanisms. Here, we employed an agent-based in silico analysis of in vivo micro-computed tomography data of prematurely aged mice to examine the effects of aging and mechanical loading on bone cells and their mechanome, the intrinsic cellular system sensing mechanical forces. Our results from applying a micro-multiphysics agent-based model to an in vivo model of premature aging (PolG) showed that aging disrupts mechanoregulation of load-induced bone formation and resorption by eliminating the increase in bone formation through diminished osteoblast activity and mineralization, alongside mechanomic alterations. Specifically, prematurely aged mice exhibited a higher frequency of quiescence at higher mechanical signals and the simulations showed that the number of lining cells and osteoclasts per bone surface increased with age. Normalized trabecular thickness was more positively associated with the ratio of osteoblast to osteoclast number (Ob.N/Oc.N) in the aged control and aged loading groups (R2=0.58 and 0.61), than in young control and loading groups (R2=0.06 and 0.27), indicating dysregulated remodeling dynamics during aging. In conclusion, our results show that in silico tools can give valuable insights into the changes in mechanoregulation and cellular mechanisms occurring under physiological and aging conditions.

synthetic biology↗

bioRxiv2026

Differential Adaptation of Osteocyte Lacunar Morphology at Bone (Re)modeling Sites under Mechanical Loading and Pharmacological Therapies in a Mouse Model of Osteoporosis

Postmenopausal osteoporosis is a highly prevalent disease characterized by low bone mass and structural deterioration of bone tissue leading to increased bone fragility and fracture risk. Osteocytes orchestrate local bone (re)modeling and therefore, characterizing their 3D morphological and spatial distribution across distinct (re)modeling microenvironments is essential for understanding the cellular mechanisms underlying divergent tissue-level responses. To address this, we used a 3D-3D multiscale registration framework mapping endpoint osteocyte lacunae onto dynamic, time-lapsed in vivo (re)modeling sites. Ovariectomized 15-week-old mice were subjected to 4 weeks of anabolic parathyroid hormone (PTH) or anti-catabolic bisphosphonate (BIS) treatment as monotreatment or combined with cyclic mechanical loading (ML). Biweekly in vivo micro-computed tomography (micro-CT) to identify (re)modeling sites and endpoint ultra-high resolution (ultra-HR) micro-CT to characterize osteocyte lacunae was performed. Osteocyte lacunae were characterized by lacunar density, volume and sphericity. Our findings showed that physical and pharmacological therapies differentially regulate the osteocyte lacunar network through distinct perilacunar adaptations across functional microenvironments. While BIS stabilizes local lacunar architecture, PTH drives asymmetrical lacunar expansion (increased volume with reduced sphericity) through perilacunar remodeling that supersedes any added ML effects. Crucially, estrogen loss disrupts the natural spatial maturation gradient by inducing rounding of lacunae in newly formed bone. Therapies counteract this disruption, restoring the healthy gradients in lacunar morphometry between spatially distinct microenvironments. Additionally, despite restoring tissue-level bone volume, physical and pharmacological osteoporosis therapies do not fully recover persistent lacunar density deficits. The overall lacunar morphological spatial signatures confirm active osteocytic tuning to endocrine, physical and matrix cues.

bioengineering↗

bioRxiv2025

Visual dependence in postural control is increased in older adults

Successful postural control depends on the integration of visual, vestibular, and proprioceptive inputs. With age, postural control degrades, leading to impaired balance and greater fall risk. Understanding how this integration changes over the lifespan is invaluable for designing more effective interventions that enable healthy postural control in older age. Earlier studies measured visual dependence using perceptual tasks or spontaneous sway comparisons across visual conditions. This study evaluates how visual dependence differs between younger and older adults within the postural control mechanism using a Central Sensorimotor Integration (CSMI) test. Eighty healthy adults (n=40, 60-87 years, n=40, 21-52 years) were exposed to small pseudorandom visual scene movements implemented in virtual reality while standing on a compliant surface. Sway responses were measured using virtual reality trackers and interpreted using an established frequency domain balance control model. Model parameters included visual weight, proportional and derivative feedback gains, time delay, and torque feedback gain. Test-retest reliability was assessed in a subgroup (n = 40) and showed excellent intra-class correlation coefficients for visual weight, proportional and derivative feedback gains (ICC = 0.89- 0.96), and lower ICCs for time delay (ICC=0.59) and torque parameters (ICC=0.39). The main difference between age groups was visual dependence, with older adults relying 40% on vision, compared to 33% for the younger group (p = 0.042). No significant group differences were found in other model parameters. Our results provide direct evidence of an increase in visual contribution to posture control with age.

neuroscience↗

bioRxiv2025

Effects of Single-Session Perturbation-Based Balance Training with Progressive Intensities on Resilience and Dynamic Gait Stability in Healthy Older Adults

Single-session perturbation-based balance training (PBT) has demonstrated improvements in dynamic stability during the initial step following perturbation in older adults. However, its broader effects on comprehensive balance recovery remain inconclusive. This pilot randomized controlled trial investigated the impact of personalized single-session PBT on reactive balance control during walking, employing advanced stability analysis techniques. Ten participants in the training group underwent a single session consisting of 32 unpredictable treadmill-induced slips and trips of progressively increasing intensity, while ten participants in the control group engaged in unperturbed treadmill walking. Key outcome measures included margin of stability (MoS) parameters: minimum MoS and the number of recovery steps, and resilience parameters: peak instability and recovery time, assessed at baseline, immediately post-intervention, and three months post-intervention following an unexpected treadmill slip. The training group exhibited significant immediate and sustained improvements (p < 0.05) in minimum MoS values, alongside a notable reduction in peak instability (p < 0.05) immediately post-intervention. These changes were not observed in the control group. However, neither group demonstrated significant alterations in the number of recovery steps or recovery time across the assessment periods. In conclusion, single-session PBT enhanced reactive balance control by improving the magnitude of post-perturbation responses, but it did not significantly influence the speed of recovery to baseline conditions.

physiology↗

bioRxiv2024

3D-bioprinted patient-specific organotypic bone model mimicking mineralization dysregulation in FKBP10-related osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heterogeneous group of rare genetic diseases characterized by increased bone fragility and deformities. The pathomechanisms of OI are poorly understood, hindering the development of disease-specific therapy. Addressing the limited understanding of OI and the lack of targeted treatments remains a challenge, given its varied symptoms and large clinical spectrum. Animal models have greatly advanced the understanding of the disease; however, the heterogeneity and subtype-specific symptoms are difficult to translate to humans. In vitro models offer a promising tool for translational medicine, as they have the potential to yield patient-specific insights in a controlled environment using patient derived-cells. We used mechanically loaded 3D-bioprinted patient-specific organotypic bone models and time-lapsed micro-computed tomography to demonstrate dysregulation of mineralization in FKBP10-related OI compared to healthy controls. In contrast to healthy controls, tissue mineral density and stiffness were decoupled, such that hypermineralization observed in OI samples did not lead to increased stiffness. Additionally, we were able to replicate experimental stiffness using sample specific micro-finite element analysis. This allowed us to show mineral formation in regions of high local strain, suggesting mechanoregulation in FKBP10-related OI organotypic bone models is comparable to healthy controls. Regional analysis of mineralization showed increased heterogeneous mineralization, microarchitectural inhomogeneities and scaffold microporosity of OI samples compared to healthy controls. Our results suggest that the observed dysregulation of mineralization is the main driver for the altered mineral-mechanics properties observed in FKBP10-related organotypic bone models. One Sentence SummaryOrganotypic bone models demonstrate dysregulated mineralization in osteogenesis imperfecta samples compared to healthy controls.

bioengineering↗

bioRxiv2024

Mechanical loading potentiates the bone response of anabolic osteoporosis treatments through mechanoregulation at the tissue level

Bones ability to adapt to mechanical demands is governed by mechanoregulation, the process by which cells sense and respond to mechanical stimuli to maintain skeletal integrity. In osteoporosis, increased bone resorption activity leads to structural deterioration and elevated fracture risk. While existing pharmacological therapies aim to restore bone mass to reduce fracture risk, it is unclear how they modulate mechanoregulation, especially when combined with physical interventions. Here, we investigate the joint effects of load-bearing physical and pharmacological treatment in a female mouse model of osteoporosis using longitudinal in vivo micro-computed tomography and computational mechanics. We demonstrate that mechanical loading additively and synergistically enhanced predicted strength, bone volume, and mechanoregulation parameters when combined with anabolic therapies (parathyroid hormone and sclerostin antibody) but not with anti-catabolic treatments (bisphosphonates). Increases in predicted strength are associated with reductions in bone resorption rates, shifts in the (re)modeling thresholds as anticipated by Frost in the mechanostat theory, and the modeling capacity of anabolic pharmacological treatments. These findings underscore the therapeutic potential of combining anabolic pharmacological therapies with load-bearing physical activity, particularly in early treatment phases, to optimize bone adaptation and fracture prevention in osteoporosis management.

bioengineering↗