Wenquan Liang

Traumatic brain injury (TBI) accelerates bone healing and induces heterotopic ossification, raising the question of whether an injured brain benefits from bone. Here we reveal that dynamic compressive tibial axial loading (DCTAL), a model of tibial bone compression, increased survival and promoted motor and cognitive recovery after stroke and TBI in mice, as well as in pig TBI models. DCTAL reduced neuron loss, attenuated chronic inflammation and astrogliosis and stimulated neuronal regeneration after TBI. Deletion of the mechanosensory channel Piezo1 in osteocytes reversed these benefits, while serum from DCTAL mice recapitulated them. Osteocytes transduced mechanical signals to directly secrete factors such as IL-1R2, APOL11a and HSP70, while indirectly increasing serum levels of BDNF, PF4 and dopamine. These factors synergistically protected against TBI. Altogether, we establish a bone–brain axis in which bone endocrine function can be modulated by mechanical forces to enhance brain repair after injury.

In metabarcoding research, such as taxon identification, phylogenetic placement plays a critical role. However, many existing phylogenetic placement methods lack comprehensive features for downstream analysis and visualization. Visualization tools often ignore placement uncertainty, making it difficult to explore and interpret placement data effectively. To overcome these limitations, we introduce a scalable approach using treeio and ggtree for parsing and visualizing phylogenetic placement data. The treeio‐ggtree method supports placement filtration, uncertainty exploration, and customized visualization. It enhances scalability for large analyses by enabling users to extract subtrees from the full reference tree, focusing on specific samples within a clade. Additionally, this approach provides a clearer representation of phylogenetic placement uncertainty by visualizing associated placement information on the final placement tree.

Abnormal subchondral bone remodeling plays a pivotal role in the progression of osteoarthritis (OA). Here, we analyzed subchondral bone samples from OA patients and observed a significant upregulation of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) specifically in subchondral bone osteoclasts. Notably, we found a strong correlation between UCHL1 expression and osteoclast activity in the subchondral bone during OA progression in both human and murine models. Conditional UCHL1 deletion in osteoclast precursors exacerbated OA progression, while its overexpression, mediated by adeno-associated virus 9, alleviated this process in male mice. Mechanistically, RANKL stimulates UCHL1 expression in osteoclast precursors, subsequently stabilizing CD13, augmenting soluble CD13 (sCD13) release, and triggering an autocrine inhibitory effect on the MAPK pathway, thereby suppressing osteoclast formation. These findings unveil a previously unidentified negative feedback loop, RANKL-UCHL1-sCD13, that modulates osteoclast formation and presents a potential therapeutic target for OA.

Although clinical evidence has indicated an association between skin atrophy and bone loss during aging, their causal relationship and the underlying mechanisms are unknown. Here we show that premature skin aging drives bone loss in mice. We further identify that cystatin-A (Csta), a keratinocyte-enriched secreted factor, mediates the effect of skin on bone. Keratinocyte-derived Csta binds the receptor for activated C-kinase 1 in osteoblast and osteoclast progenitors, thus promoting their proliferation but inhibiting osteoclast differentiation. Csta secretion decreases with skin aging in both mice and humans, thereby causing senile osteoporosis by differentially decreasing the numbers of osteoblasts and osteoclasts. In contrast, topical application of calcipotriol stimulates Csta production in the epidermis and alleviates osteoporosis. These results reveal a mode of endocrine regulation of bone metabolism in the skin, and identify Csta as an epidermally derived hormone linking skin aging to age-related bone loss. Enhancers of skin Csta levels could serve as a potential topical drug for treatment of senile osteoporosis.

Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts, blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating factors. Due to these adverse effects, preosteoblast senescence is a crucial target for the treatment of age-related bone loss; however, the underlying mechanism remains unclear. We found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse model. Mechanistically, mTORC1 induced a change in the membrane potential from polarization to depolarization, thus promoting cell senescence by increasing Ca²⁺influx and activating downstream NFAT/ATF3/p53 signaling. We further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent preosteoblasts. Scn1a expression was found to be positively regulated by mTORC1 upstream of C/EBPα, whereas its permeability to Na⁺was found to be gated by protein kinase A (PKA)-induced phosphorylation. Prosenescent stresses increased the permeability of Scn1a to Na⁺by suppressing PKA activity and induced depolarization in preosteoblasts. Together, our findings identify a novel pathway involving mTORC1, Scn1a expression and gating, plasma membrane depolarization, increased Ca²⁺influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast senescence. Pharmaceutical studies of the related pathways and agents might lead to novel potential treatments for age-related bone loss.

Introduction: Estrogen deficiency leads to bone loss in postmenopausal osteoporosis, because bone formation, albeit enhanced, fails to keep pace with the stimulated osteoclastic bone resorption. The mechanism driving this uncoupling is central to the pathogenesis of postmenopausal osteoporosis, which, however, remains poorly understood. We previously found that Cxcl9 secreted by osteoblasts inhibited osteogenesis in bone, while the roles of Cxcl9 on osteoclastic bone resorption and osteoporosis are unclear. Materials and Methods: Postmenopausal osteoporosis mouse model was established by bilateral surgical ovariectomy (OVX). In situ hybridization was performed to detect Cxcl9 mRNA expression in bone. ELISA assay was conducted to assess Cxcl9 concentrations in bone and serum. Cxcl9 activity was blocked by its neutralizing antibody. Micro-CT was performed to determine the effects of Cxcl9 neutralization on bone structure. Cell Migration and adhesion assay were conducted to evaluate the effects of Cxcl9 on osteoclast activity. TRAP staining and Western blot were performed to assess osteoclast differentiation. CXCR3 antagonist NBI-74,330 or ERK antagonist SCH772984 was administered to osteoclast to study the effects of Cxcl9 on CXCR3/ERK signaling. Results: Cxcl9 was expressed and secreted increasingly in OVX mice bone. Neutralizing Cxcl9 in bone marrow prevented bone loss in the mice by facilitating bone formation as well as inhibiting bone resorption. In vitro, Cxcl9 secreted from osteoblasts facilitated osteoclast precursors adhesion, migration and their differentiation into mature osteoclasts. The positive role of osteoblastic Cxcl9 on osteoclasts was eliminated by blocking CXCR3/ERK signaling in osteoclasts. Estrogen negatively regulated Cxcl9 expression and secretion in osteoblasts, explaining the increased Cxcl9 concentration in OVX mice bone. Conclusion: Our study illustrates the roles of Cxcl9 in inhibiting bone formation and stimulating bone resorption in osteoporotic bone, therefore providing a possible therapeutic target to the treatment of postmenopausal osteoporosis.