Biology subjects

Miller, R. E.

Publications and source records attributed to Miller, R. E..

3 recordsLinked to original sources

bioRxiv2022

Age-associated changes in knee osteoarthritis, pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice

ObjectiveOsteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. While injury-induced OA models are useful, only a subset of OA is linked to traumatic injury. Here, we aimed to characterize age-associated joint damage, mechanical sensitization, and dorsal root ganglia (DRG) immune phenotypes in mice of both sexes. MethodsMale or female mice aged 6- or 20-months old were evaluated for histopathologic knee OA, pain-related behaviors, and L3-L5 dorsal root ganglia (DRG) immune characterization via flow cytometry. DRG gene expression in aged mice and humans was also examined. ResultsTwenty-month old male mice had worse cartilage degeneration than 6-month old mice. Older female knees showed increased cartilage degeneration, but to a lesser degree than males. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells, and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male DRGs showed increased expression of Ccl2 and Ccl5 and older female DRGs showed increased Cxcr4 and Ccl3 compared to 6-month DRGs, among other differentially expresssed genes. Human DRG analysis from six individuals >80 years old revealed elevated CCL2 in male DRGs compared to females, whereas CCL3 was higher in female DRGs. ConclusionsHere we show that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of analgesic therapies.

cell biology↗

bioRxiv2022

Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis

Osteoarthritis is a very common painful joint disease, for which few treatment options exist. New non-opioid targets are needed for addressing osteoarthritis pain, which is mechanical in nature and associated with daily activities such as walking and climbing stairs. Piezo2 has been implicated in development of mechanical pain, but the mechanisms by which this occurs remain poorly understood. We observed that in two different murine models of osteoarthritis (destabilization of the medial meniscus and natural aging), nociceptor-specific Piezo2 conditional knock-out mice developed osteoarthritic joint damage, but were protected from associated mechanical sensitization. Since nerve growth factor (NGF) is known to mediate nociceptor sensitization, and antibodies that neutralize NGF are effective as a treatment for osteoarthritis pain, we explored the effects of intra-articularly injected NGF on the development of mechanical joint pain. Wild-type mice developed knee swelling and mechanical pain in response to intra-articular NGF, while nociceptor-specific Piezo2 conditional knock-out mice were protected from these effects. Single cell RNA sequencing and in situ hybridization of mouse and human lumbar dorsal root ganglia (DRG) revealed that a subset of nociceptors co-express Piezo2 and Ntrk1 (the gene that encodes the NGF receptor TrkA). These results indicate that Piezo2 plays a key role in nociceptor sensitization processes in the osteoarthritic joint, and targeting Piezo2 may represent a novel therapy for osteoarthritis pain control. One Sentence SummaryNociceptor sensitization to mechanical stimuli is dependent on Piezo2 in mouse models of osteoarthritis.

physiology↗

bioRxiv2021

Diversification of ergot alkaloids and heritable fungal symbionts in morning glories

Heritable microorganisms play critical roles in life cycles of many macro-organisms but their prevalence and functional roles are unknown for most plants. Bioactive ergot alkaloids produced by heritable Periglandula fungi occur in some morning glories (Convolvulaceae), similar to ergot alkaloids in grasses infected with related fungi. Ergot alkaloids have been of longstanding interest given their toxic effects, psychoactive properties, and medical applications. Here we show that ergot alkaloids are concentrated in four morning glory clades exhibiting differences in alkaloid profiles and are more prevalent in species with larger seeds than those with smaller seeds. Further, we found a phylogenetically-independent, positive correlation between seed mass and alkaloid concentrations in symbiotic species. Our findings suggest that heritable symbiosis has diversified among particular clades by vertical transmission through seeds combined with host speciation, and that ergot alkaloids are particularly beneficial to species with larger seeds. Our results are consistent with the defensive symbiosis hypothesis where bioactive ergot alkaloids from Periglandula symbionts protect seeds and seedlings from natural enemies, and provide a framework for exploring microbial chemistry in other plant-microbe interactions.

plant biology↗