Antibiotic-induced shifts in the indigenous gut microbiota influence normal skeletal maturation. Current theory implies that gut microbiota actions on bone occur through a direct gut/bone signaling axis. However, our prior work supports that a gut/liver signaling axis contributes to gut microbiota effects on bone. Our purpose was to investigate the effects of minocycline, a systemic antibiotic treatment for adolescent acne, on pubertal/postpubertal skeletal maturation. Sex-matched specific pathogen–free (SPF) and germ-free (GF) C57BL/6T mice were administered a clinically relevant minocycline dose from age 6–12 weeks. Minocycline caused dysbiotic shifts in the gut bacteriome and impaired skeletal maturation in SPF mice but did not alter the skeletal phenotype in GF mice. Minocycline administration in SPF mice disrupted the intestinal farnesoid X receptor/fibroblast growth factor 15 axis, a gut/liver endocrine axis supporting systemic bile acid homeostasis. Minocycline-treated SPF mice had increased serum conjugated bile acids that were farnesoid X receptor (FXR) antagonists, suppressed osteoblast function, decreased bone mass, and impaired bone microarchitecture and fracture resistance. Stimulating osteoblasts with the serum bile acid profile from minocycline-treated SPF mice recapitulated the suppressed osteogenic phenotype found in vivo, which was mediated through attenuated FXR signaling. This work introduces bile acids as a potentially novel mediator of gut/liver signaling actions contributing to gut microbiota effects on bone.

Low back pain is a widespread condition that significantly impacts quality of life, with intervertebral disc degeneration (IDD) being a major contributing factor. However, the underlying mechanisms of IDD remain poorly understood, necessitating further investigation. Environmental risk factors, such as mechanical stress and cigarette smoke, elevate reactive oxygen species levels from both endogenous and exogenous sources, leading to redox imbalance and oxidative stress. The endoplasmic reticulum (ER) and mitochondria, two key organelles responsible for protein folding and energy production, respectively, are particularly vulnerable to oxidative stress. Under oxidative stress conditions, ER stress and mitochondrial dysfunction occur, resulting in unfolded protein response activation, impaired biosynthetic processes, and disruptions in the tricarboxylic acid cycle and electron transport chain, ultimately compromising energy metabolism. Prolonged and excessive ER stress can further trigger apoptosis through ER–mitochondrial crosstalk. Given the unique microenvironment of the intervertebral disc (IVD)—characterized by hypoxia, glucose starvation, and region-specific cellular heterogeneity—the differential effects of environmental stressors on distinct IVD cell populations require further investigation. This review explores the potential mechanisms through which environmental risk factors alter IVD cell activities, contributing to IDD progression, and discusses future therapeutic strategies aimed at mitigating disc degeneration.

Clarifying multifactorial musculoskeletal disorder etiologies supports risk analysis, development of targeted prevention, and treatment modalities. Deep learning enables comprehensive risk factor identification through systematic analyses of disease data sets but does not provide sufficient context for mechanistic understanding, limiting clinical applicability for etiological investigations. Conversely, multiscale biomechanical modeling can evaluate mechanistic etiology within the relevant biomechanical and physiological context. We propose a hybrid approach combining 3D explainable deep learning and multiscale biomechanical modeling; we applied this approach to investigate temporomandibular joint (TMJ) disorder etiology by systematically identifying risk factors and elucidating mechanistic relationships between risk factors and TMJ biomechanics and mechanobiology. Our 3D convolutional neural network recognized TMJ disorder patients through participant-specific morphological features in condylar, ramus, and chin. Driven by deep learning model outputs, biomechanical modeling revealed that small mandibular size and flat condylar shape were associated with increased TMJ disorder risk through increased joint force, decreased tissue nutrient availability and cell ATP production, and increased TMJ disc strain energy density. Combining explainable deep learning and multiscale biomechanical modeling addresses the “mechanism unknown” limitation undermining translational confidence in clinical applications of deep learning and increases methodological accessibility for smaller clinical data sets by providing the crucial biomechanical context.

The cartilage endplates (CEPs) on the superior and inferior surfaces of the intervertebral disc (IVD), are the primary nutrient transport pathways between the disc and the vertebral body. Passive diffusion is responsible for transporting small nutrient and metabolite molecules through the avascular CEPs. The baseline solute diffusivities in healthy CEPs have been previously studied, however alterations in CEP diffusion associated with IVD degeneration remain unclear. This study aimed to quantitatively compare the solute diffusion in healthy and degenerated human CEPs using a fluorescence recovery after photobleaching (FRAP) approach. Seven healthy CEPs and twenty-two degenerated CEPs were collected from five fresh-frozen human cadaveric spines and seventeen patients undergoing spine fusion surgery, respectively. The sodium fluorescein diffusivities in CEP radial and vertical directions were measured using the FRAP method. The CEP calcification level was evaluated by measuring the average X-ray attenuation. No difference was found in solute diffusivities between radial and axial directions in healthy and degenerated CEPs. Compared to healthy CEPs, the average solute diffusivity was 44% lower in degenerated CEPs [Healthy: 29.07(23.96-33.62) µm²/s; Degenerated: 16.32(13.84-18.84) µm²/s, p<0.001]. The average solute diffusivity had an inverse relationship with the degree of CEP calcification as determined by the normalized X-ray attenuation values. This study suggests that solute diffusion through the disc and vertebral body interface is significantly hindered by CEP calcification, providing clues to help further understand the IVD degeneration mechanism.

Natural protective materials offer unparalleled solutions for impact-resistant material designs that are simultaneously lightweight, strong, and tough. Particularly, the Bouligand structure found in the dactyl club of mantis shrimp and the staggered structure in nacre achieve excellent mechanical strength, toughness, and impact resistance. Previous studies have shown that hybrid designs by combining different bioinspired microstructures can lead to enhanced mechanical strength and energy dissipation. Nevertheless, it remains unknown whether combining Bouligand and staggered structures in nanofibrillar cellulose (NFC) films, forming a discontinuous fibrous Bouligand (DFB) architecture, can achieve enhanced impact resistance against projectile penetration. Additionally, the failure mechanisms under such dynamic loading conditions have been minimally understood. In our study, we systematically investigate the dynamic failure mechanisms and quantify the impact resistance of NFC thin films with DFB architecture by leveraging previously developed coarse-grained models and ballistic impact molecular dynamics simulations. We find that when nanofibrils achieve a critical length and form DFB architecture, the impact resistance of NFC films outperforms the counterpart films with continuous fibrils by comparing their specific ballistic limit velocities and penetration energies. We also find that the underlying mechanisms contributing to this improvement include enhanced fibril sliding, intralayer and interlayer crack bridging, and crack twisting in the thickness direction enabled by the DFB architecture. Our results show that by combining Bouligand and staggered structures in NFC films, their potential for protective applications can be further improved. Our findings can provide practical guidelines for the design of protective films made of nanofibrils.