Biology subjects

Ackert-Bicknell, C. L.

Publications and source records attributed to Ackert-Bicknell, C. L..

7 recordsLinked to original sources

bioRxiv2026

Bone response to intermittent parathyroid hormone (PTH) is both genetic and sex specific

Teriparatide (PTH 1-34) is an anabolic agent used to treat osteoporosis, yet clinical response varies widely among patients. To investigate genetic and sex-specific determinants of skeletal response, we administered intermittent PTH to male and female mice from eight genetically diverse inbred strains. Mice were treated for four weeks, and bone phenotypes were assessed via DXA, microCT, and mechanical testing. Response to PTH was highly strain- and sex-dependent, with some strains responding at the femur but not the spine, and vice versa. Heritability estimates for PTH-induced changes in areal bone mineral density (aBMD), cortical bone area at the femoral mid-diaphysis, femur strength, and trabecular bone volume fraction (BV/TV) ranged from moderate to high, with BV/TV showing the strongest genetic influence. Cortical bone response mechanisms differed by sex: males exhibited periosteal expansion, while females showed endosteal remodeling. These findings mirror clinical observations where non-response to PTH can be anatomic site specific. Further, our study suggests that genetic background and sex significantly influence bone response to PTH. Our data support the future use of genetically diverse mouse models to elucidate the genetic architecture of skeletal response to PTH.

genetics↗

bioRxiv2026

Microbial Influenced Corrosion: A Novel Initiator of In Vivo Spine Rod Fracture

ABSTRACTSpine rod catastrophic failure/rod fracture after implantation is estimated to occur in [~]10% of all cases worldwide with this rate remaining consistent for more than 20 years. To accommodate the spine mechanical environment, metal alloys such as austenitic stainless steels, cobalt-chromium-molybdenum alloys, and /{beta} type titanium alloys such are used as they have a high resistance to fatigue failure. The work presented herein addresses the gap in understanding about what happens in a laboratory environment versus what is happening in human patients that results in metal leaching into tissues as well as a shortened lifespan of a spine rod in a patient population that is not capable of breaking these spine rods from purely mechanical means. Eighty-five (N=85) patients (51 female - 62.9 {+/-} 13.5 years old, 34 male - 62.7 {+/-} 10.9 years old) who had spine revision surgery due to patient mechanical issues, such as loss of sagittal or coronal balance, pain, pedicle screw loosening, hardware associated infection were included in this study. All explanted rods had optical indications of surface modification that were not the result of mechanical damage, e.g. gouges, scratches, notches. The presence of Ti6Al4V rods increases the presence of local tissue concentrations of elemental Ti (190.98 {+/-} 207.84 g/g (ppm)) in all patients over the amount that would normally be present in patients who never had any titanium based orthopedic device implants (spinous muscle, 13.12 {+/-} 11.43 g/g). PQS, HHQ, and NHQ ToF-SIMS molecular signals were found co-located to corrosion pits as well with AHLs and palmitic acids indicating microbial presence and metabolism in all patients. This suggests that MIC can cause in vivo pitting corrosion resulting on rod failure.

bioengineering↗

bioRxiv2024

GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density

Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. Informed by a variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed a single-cell CRISPRi screen in human fetal osteoblasts (hFOBs). The BMD relevance of hFOBs was supported by heritability enrichment from stratified LD-score regression involving 98 cell types grouped into 15 tissues. 23 genes showed perturbation in the screen, with four (ARID5B, CC2D1B, EIF4G2, and NCOA3) exhibiting consistent effects upon siRNA knockdown on three measures of osteoblast maturation and mineralization. Lastly, additional heritability enrichments, genetic correlations, and multi-trait fine-mapping revealed unexpectedly that many BMD GWAS signals are pleiotropic and likely mediate their effects via non-bone tissues. Extending our CRISPRi screening approach to these tissues could play a key role in fully elucidating the etiology of BMD.

genomics↗

bioRxiv2022

Detecting isoform-level allelic imbalance accounting for inferential uncertainty

Allelic imbalance (AI) of gene expression in heterozygous individuals is a hallmark of cis-genetic regulation, revealing mechanisms underlying the association of non-coding genetic variation with downstream traits, as in GWAS. Most methods for detecting AI from RNA-sequencing (RNA-seq) data examine allelic expression per exonic SNP, which may obscure imbalance in expression of individual isoforms. Detecting AI at the isoform level requires accounting for inferential uncertainty (IU) of expression estimates, caused by multi-mapping of RNA-seq reads to isoforms and alleles. Swish, a method developed previously for differential transcript expression accounting for IU, can be applied in a paired setting to detect AI. However, in AI analysis, most transcripts will have high IU across alleles such that even methods like Swish will lose power. Our proposed method, SEESAW, offers AI analysis at various level of resolution, including gene level, isoform level, and optionally aggregating isoforms within a gene based on their transcription start site (TSS). This TSS-based aggregation strategy strengthens the signal for transcripts that may have high IU with respect to allelic quantification. SEESAW is primarily designed for experiments with multiple replicates or conditions of organisms with the same genotype, as in an F1 cross or time course experiments of cell lines. Additionally, we introduce a new test for detecting AI that changes across a continuous covariate, as in a time course experiment. The SEESAW suite of methods is evaluated both on simulated data and applied to an RNA-seq dataset of differentiating F1 mouse osteoblasts.

bioinformatics↗

bioRxiv2022

Whole-Genome RNA Sequencing of Femoral Head Impingement Cartilage Identifies FGF18 As A Biomarker in Hip Osteoarthritis Progression

IntroductionThe natural history of Femoroacetabular Impingement (FAI) has been clinically associated with the development of hip osteoarthritis (OA); however, the pathobiological mechanisms underlying the transition from focal impingement to global joint degeneration remain unclear. The goal of the study was to investigate differences in transcriptomic profiles of the cartilage from FAI and hip OA patients using whole-genome RNA sequencing. MethodsThirty-seven patients were included in the study with 20 diagnosed with FAI undergoing arthroscopic treatment and 15 diagnosed with hip OA undergoing total hip arthroplasty (THA). Cartilage samples were obtained intraoperatively over the femoral head-neck junction for both FAI and OA cohorts. Whole-genome RNA sequencing was performed on 10 gender-matched patients in the FAI and OA cohorts with the remaining samples used for histopathologic analysis using the Osteoarthritis Research Society International (OARSI) grading system and qRT-PCR validation. Target validation was further confirmed with immunohistochemical staining for FGF18 on FAI and OA cartilage samples. ResultsWe identified a total of 3,531 Differentially Expressed Genes (DEGs) between the FAI and OA cohorts with multiple targets for genes implicated in canonical OA pathways. qRT-PCR validation confirmed increased expression of FGF18 and WNT16 in the FAI samples, while there was increased expression of MMP13 and ADAMTS4 in the OA samples. Expression levels of FGF18 and WNT16 were also higher in FAI samples with mild cartilage damage (OARSI grades 1-2) compared to FAI samples with severe cartilage damage or OA cartilage (OARSI grade 4-6). Immunohistochemical evaluation identified increased FGF18 staining in OARSI grade 1-2 FAI samples compared to OARSI grade 5-6 FAI and OA samples. ConclusionsRNA sequencing of cartilage of FAI and hip OA patients identified a negative association of FGF18 expression levels with cartilage damage severity, suggesting that FGF18 may be used as a marker for hip OA progression. Future evaluation of FGF18 signaling as well as other markers in early OA may yield further insight into disease prevention and treatment.

bioinformatics↗

bioRxiv2019

Genetic Analysis of Osteoblast Activity Identifies Zbtb40 as a Regulator of Osteoblast Activity and Bone Mass

Osteoporosis is a genetic disease characterized by progressive reductions in bone mineral density (BMD) leading to an increased risk of fracture. Over the last decade, genome-wide association studies (GWASs) have identified over 1000 associations for BMD. However, as a phenotype BMD is challenging as bone is a multicellular tissue affected by both local and systemic physiology. Here, we focused on a single component of BMD, osteoblast-mediated bone formation in mice, and identified associations influencing osteoblast activity on mouse Chromosomes (Chrs) 1, 4, and 17. The locus on Chr. 4 was in an intergenic region between Wnt4 and Zbtb40, homologous to a locus for BMD in humans. We tested both Wnt4 and Zbtb40 for a role in osteoblast activity and BMD. Knockdown of Zbtb40, but not Wnt4, in osteoblasts drastically reduced mineralization. Additionally, loss-of-function mouse models for both genes exhibited reduced BMD. Our results highlight that investigating the genetic basis of in vitro osteoblast mineralization can be used to identify genes impacting bone formation and BMD.

genetics↗

bioRxiv2019

Identification of a core module for bone mineral density through the integration of a co-expression network and GWAS data

Recently, the \"omnigenic\" model of the genetic architecture of complex traits proposed two general categories of causal genes, core and peripheral. Core genes are hypothesized to play a direct role in regulating disease; thus, their identification has the potential to reveal critical regulators and novel therapeutic targets. Here, we sought to identify genes with \"core-like\" characteristics for bone mineral density (BMD), one of the most significant predictors of osteoporotic fracture. This was accomplished by analyzing genome-wide association study (GWAS) data through the lens of a cell-type and timepoint-specific gene co-expression network for mineralizing osteoblasts. We identified a single co-expression network module that was enriched for genes implicated by GWAS and partitioned BMD heritability, correlated with in vitro osteoblast mineralization, and enriched for genes, which when mutated in humans or mice, led to a skeletal phenotype. Further characterization of this module identified four novel genes (B4GALNT3, CADM1, DOCK9, and GPR133) located within BMD GWAS loci with colocalizing expression quantitative trait loci (eQTL) and altered BMD in mouse knockouts, suggesting they are causal genetic drivers of BMD in humans. Our network-based approach identified a \"core\" module for BMD and provides a resource for expanding our understanding of the genetics of bone mass.

genetics↗