Finite element modelling is well entrenched in comparative vertebrate biomechanics as a tool to assess the mechanical design of skeletal structures and to better comprehend the complex interaction of their form–function relationships. But what makes a reliable subject-specific finite element model? To approach this question, we here present a set of convergence and sensitivity analyses and a validation study as an example, for finite element analysis (FEA) in general, of ways to ensure a reliable model. We detail how choices of element size, type and material properties in FEA influence the results of simulations. We also present an empirical model for estimating heterogeneous material properties throughout an elephant femur (but of broad applicability to FEA). We then use an ex vivo experimental validation test of a cadaveric femur to check our FEA results and find that the heterogeneous model matches the experimental results extremely well, and far better than the homogeneous model. We emphasize how considering heterogeneous material properties in FEA may be critical, so this should become standard practice in comparative FEA studies along with convergence analyses, consideration of element size, type and experimental validation. These steps may be required to obtain accurate models and derive reliable conclusions from them.

What makes an accurate and reliable subject-specific finite element model? A case study of an elephant femur (Retraction of vol 9, pg 351, 2012)

Hyaluronan (HA) is a large but simple glycosaminoglycan composed of repeating D-glucuronic acid, beta1-3 linked to N-acetyl-D-glucosamine beta1-4, found in body fluids and tissues, in both intra- and extracellular compartments. Despite its structural simplicity, HA has diverse functions in skeletal biology. In development, HA-rich matrices facilitate migration and condensation of mesenchymal cells, and HA participates in joint cavity formation and longitudinal bone growth. In adult cartilage, HA binding to aggrecan immobilises aggrecan, retaining it at the high concentrations required for compressive resilience. HA also appears to regulate bone remodelling by controlling osteoclast, osteoblast and osteocyte behaviour. The functions of HA depend on its intrinsic properties, which in turn rely on the degree of polymerisation by HA synthases, depolymerisation by hyaluronidases, and interactions with HA-binding proteins. HA synthesis and degradation are closely regulated in skeletal tissues and aberrant synthetic or degradative activity causes disease. The role and regulation of HA synthesis and degradation in cartilage, bone and skeletal development is discussed.

Hyaluronan synthesis and degradation in cartilage and bone.

Osteoarthritis (OA) is the most common form of arthritis. It is characterized by progressive destruction of articular cartilage and the development of chronic pain and constitutes a considerable socioeconomic burden. Currently, pharmacological treatments mostly aim to relieve the OA symptoms associated with inflammation and pain. However, with increasing understanding of OA pathology, several potential therapeutic targets have been identified, enabling the development of disease-modifying OA drugs (DMOADs). By targeting inflammatory cytokines, matrix-degrading enzymes, the Wnt pathway, and OA-associated pain, DMOADs successfully modulate the degenerative changes in osteoarthritic cartilage. Moreover, regenerative approaches aim to counterbalance the loss of cartilage matrix by stimulating chondrogenesis in endogenous stem cells and matrix anabolism in chondrocytes. Emerging strategies include the development of senolytic drugs or RNA therapeutics to eliminate the cellular or molecular sources of factors driving OA. This review describes the current developmental status of DMOADs and the corresponding results from preclinical and clinical trials and discusses the potential of emerging therapeutic approaches to treat OA.

Disease-modifying therapeutic strategies in osteoarthritis: current status and future directions

Background: Knee osteoarthritis (KOA) is one of the most common chronic musculoskeletal disorders worldwide, for which exosomes derived from stem cells may provide an effective treatment. Purpose: To assess the effect of exosomes derived from human urine–derived stem cells (hUSCs) overexpressing miR-140-5p (miR means microRNA) on KOA in an in vitro interleukin 1β (IL-1β)–induced osteoarthritis (OA) model and an in vivo rat KOA model. Study Design: Controlled laboratory study. Methods: Exosomes derived from hUSCs (hUSC-Exos) were isolated and validated. The hUSCs were transfected with miR-140s using lentivirus, and exosomes secreted from such cells (hUSC-140-Exos) were collected. The roles of hUSC-Exos and hUSC-140-Exos in protecting chondrocytes against IL-1β treatment were compared by analyzing the proliferation, migration, apoptosis, and secretion of extracellular matrix (ECM) in chondrocytes. After vascular endothelial growth factor A (VEGFA) was identified as a target of miR-140, the mechanism by which VEGFA can mediate the beneficial effect of miR-140 on OA was investigated using small interfering RNA transfection or chemical drugs. The expression of VEGFA in cartilage and synovial fluid from patients with KOA was measured and compared with that of healthy controls. Surgery for anterior cruciate ligament transection and destabilization of the medial meniscus were performed on the knee joints of Sprague-Dawley rats to establish an animal model of OA, and intra-articular (IA) injection of hUSC-Exos or hUSC-140-Exos was conducted at 4 to 8 weeks after the surgery. Cartilage regeneration and subchondral bone remodeling were evaluated through histological staining and micro–computed tomography analysis. Results: Proliferation and migration ability were enhanced and apoptosis was inhibited in chondrocytes treated with IL-1β via hUSC-Exos, with the side effect of decreased ECM secretion. hUSC-140-Exos not only retained the advantages of hUSC-Exos but also increased the secretion of ECM by targeting VEGFA, including collagen II and aggrecan. Increased expression of VEGFA during the progression of KOA was also confirmed in cartilage and synovial fluid samples obtained from patients with OA. In the rat OA model, IA injection of hUSC-140-Exos enhanced cartilage regeneration and subchondral bone remodeling. Conclusion: Our results demonstrated the superiority of hUSC-Exos overexpressing miR-140-5p for treating OA compared with the hUSC-Exos. The effect of hUSC-140-Exos for suppressing the progression of KOA is in part mediated by VEGFA. Clinical Relevance: Exosomes derived from stem cells may provide a promising treatment for KOA, and our study can advance the related basic research.

Exosomes Derived From Human Urine–Derived Stem Cells Overexpressing miR-140-5p Alleviate Knee Osteoarthritis Through Downregulation of VEGFA in a Rat Model

MicroRNAs are short endogenous non-coding RNA molecules, typically 19-25 nucleotides in length, which negatively regulate gene expression. In osteoarthritis (OA), several genes necessary for cartilage homeostasis are aberrantly expressed, with a number of miRNAs implicated in this process. However, our knowledge of the earliest stages of OA, prior to the onset of irreversible changes, remains limited. The purpose of this study was to identify miRNAs involved across the time-course of OA using both a murine model and human cartilage, and to define their function.
Expression profile of miRNAs (Exiqon) and mRNAs (Illumina) on total RNA purified from whole knee joints taken from mice which underwent destabilisation of the medial meniscus (DMM) surgery at day 1, 3 and 7 post-surgery showed: the miRNA expression in whole mouse joints post DMM surgery increased over 7 days; at day 1 and 3, the expression of only 4 miRNAs altered significantly; at day 7, 19 miRNAs were upregulated and 15 downregulated. Among the modulated miRNAs, the miR-29b was the most interesting and was chosen to further investigate since integrating analysis of the miRNA and mRNA expression array data showed the inverse correlation between miR-29b and its
potential targets. In end-stage human OA cartilage and in murine injury model, the miR-29 family was found to increase expression. Moreover, the miR-29 family was found to be the negative regulator in both human and murine chondrogenesis, and was also found to involve in murine limb development. Expression of the miR-29 family was found to
suppress by SOX9 at least in part through directly binding to the promoter of the primary miR-29a/b1. Also, TGFβ1/3 decreased expression of the miR-29 family whilst Wnt3a did not have any effect. Lipopolysaccharide suppressed the miR-29 family expression in part
through NFκB signalling pathway while the IL-1 strongly induced its expression partly through P38 MAKP signalling. Using luciferase reporter assay, the miR-29 family was showed to suppress the TGFβ, NFκB, and WNT/β-catenin signalling pathways. Gene expression profiles of gain- and-loss-of-function revealed regulation of a large number of previously recognised extracellular matrix-associated genes as well as an additional subset of protease and Wnt signalling pathway-related genes. Among these genes, ADAMTS6, ADAMTS10, ADAMTS14, ADAMTS17, ADAMTS19, FZD3, DVL3, FRAT2, CK2A2 were experimentally validated as direct targets of the miR-29 family.

The roles of the microrna 29 family in cartilage homeostasis and osteoarthritis

Cryptotanshinone (CTS) has emerged as an anti-inflammatory agent in osteoarthritis (OA). However, the molecular mechanism underlying its potent therapeutic effect on OA remains largely unknown. MicroRNAs (miRNAs) act as crucial regulators in maintaining cartilage homeostasis. To investigate whether CTS protects against developing OA through regulation of miRNAs, we examined the potential CTS-mediated miRNA molecules using microarray analysis. We found that CTS significantly promoted miR-106a-5p expression in chondrocytes. Using the OA mouse model created by anterior cruciate ligament transection, we revealed that intra-articular injection of miR-106a-5p agomir attenuated OA. In addition, miR-106a-5p inhibited GLI-similar 3 (GLIS3) production by directly targeting the 3' untranslated region. CTS promoted miR-106a-5p expression through recruitment of a member of the paired box (PAX) family of transcription factors, PAX5, to the miR-106a-5p promoter. Inhibition of PAX5 mimicked the effect of miR-106a-5p and abolished the CTS ability to regulate miR-106a-5p expression. In OA patients, miR-106-5p is downregulated which is accompanied by downregulation of PAX5 and upregulation of GLIS3. Collectively, these data highlight that the PAX5/miR-106a-5p/GLIS3 axis acts as a novel pleiotropic regulator in CTS-mediated OA cartilage protection, suggesting that miR-106a-5p and PAX5 activation and GLIS3 inhibition might be useful and attractive for therapeutic strategies to treat OA patients.

Cryptotanshinone Protects Cartilage against Developing Osteoarthritis through the miR-106a-5p/GLIS3 Axis

OBJECTIVE
The connection between alterations in the disc structure following percutaneous endoscopic lumbar discectomy (PELD) and symptoms in patients postsurgery has not been reported yet. The purpose of the present study was to discuss the potential correlation between the changes in the morphological characteristics of various reference surfaces of the intervertebral disc after percutaneous endoscopic lumbar discectomy (PELD) and clinical outcomes, to identify the morphological parameters that affect efficacy and provide an evidence-based foundation for assessing postoperative efficacy.


METHODS
From October 2019 to October 2021, after percutaneous endoscopic lumbar discectomy (PELD), 98 individuals were enrolled. MRI DICOM data of the lumbar spine were obtained before and after surgery, specifically around 3 months. The morphological parameters of the operated and adjacent segments of the discs were measured using T2-weighted images from three reference planes. Outcomes were assessed using the Oswestry disability index (ODI), visual analogue pain scores for the back and leg (VAS-back/VAS-leg), Japanese Orthopaedic Association (JOA) scores, and recovery rates. Postoperative changes in disc parameters and outcomes were compared between patients with different severity and types of LDH based on the MSU staging. Patients completed the questionnaire during outpatient follow-up appointments 3, 6, and 12 months after the surgery. The follow-up period was 14.69 ± 4.21 months, ranging from 12 to 24 months.


RESULTS
Parameters such as area and circumference of intervertebral discs in the cross-section were not associated with the change in the efficacy index. Postoperatively, a negative correlation between the variation of the disc height, disc height index, and protrusion distance and the difference in VAS scores for low back pain at 3 and 6 months was observed among the two sagittal change parameters. Differences between changes in disc imaging parameters and postoperative efficacy were not statistically significant between various types of lumbar disc herniation.


CONCLUSION
For the patients after percutaneous endoscopic lumbar discectomy, the changes in parameters such as disc area and circumference in the cross-sectional plane are not associated with efficacy, and the changes in disc height and herniation distance in the sagittal plane provide a morphologic basis for the assessment of short-term postoperative efficacy. In addition, the changes in disc morphologic parameters and postoperative efficacy do not differ between various types of lumbar disc herniation.

Correlation between Disc Imaging Observations and Clinical Efficacy after Percutaneous Endoscopic Lumbar Discectomy: A 1-Year Follow-up Study.

•This is a diagnostic study for a classification for posterior spinal osteotomy procedures via the intervertebral space.•Proposed ​a novel classification ​with ​excellent reliability ​and ​validity, differ from the SRS-Schwab osteotomy classification.•Give a novel definition of "trans-intervertebral osteotomy" (TIO) for posterior spinal osteotomy procedures.•Thoroughly discussed about the histories of posterior spinal osteotomy procedures via the intervertebral space.•Systematically introduced the TIO technique with fine original schematics. 

https://doi.org/10.1016/j.bas.2022.101707

Trans-intervertebral osteotomy classification of posterior spinal corrective osteotomy procedures via the intervertebral space

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Cryptotanshinone Protects Cartilage against Developing Osteoarthritis through the miR-106a-5p/GLIS3 Axis

Correlation between Disc Imaging Observations and Clinical Efficacy after Percutaneous Endoscopic Lumbar Discectomy: A 1-Year Follow-up Study.

Trans-intervertebral osteotomy classification of posterior spinal corrective osteotomy procedures via the intervertebral space