Biology subjects

van der Meulen, M. C. H.

Publications and source records attributed to van der Meulen, M. C. H..

3 recordsLinked to original sources

bioRxiv2022

Impaired ERK MAPK activation in mature osteoblasts enhances bone formation via the mTOR pathway

Emerging evidence supports that osteogenic differentiation of skeletal stem cells (SSCs) is a key determinant of overall bone formation and bone mass. Despite extensive studies showing mitogen-activated protein kinase (MAPK) function in osteoblast differentiation, none of these studies properly show in vivo evidence of impacting post-lineage commitment and subsequent maturation. Here, we describe how the extracellular signal-regulated kinase (ERK) pathway in osteoblasts controls bone formation by suppressing the mechanistic target of rapamycin (mTOR) pathway. We also show that, while ERK inhibition blocks the differentiation of osteogenic precursors when initiated at an early stage, ERK inhibition surprisingly promotes the later stages of osteoblast differentiation. Accordingly, inhibition of the ERK pathway using a small compound inhibitor or conditional deletion of the MAP2Ks Mek1 and Mek2, in mature osteoblasts and osteocytes (Mek1/2Dmp1), markedly increased bone formation due to augmented osteoblast differentiation. Mice with inducible deletion of the ERK pathway in mature osteoblasts (Mek1/2Ocn-Ert) also displayed similar phenotypes, demonstrating that this phenotype reflects continuous postnatal inhibition of late-stage osteoblast maturation. Mechanistically, ERK inhibition increases mitochondrial function and SGK1 phosphorylation via mTOR2 activation, which leads to osteoblast differentiation and production of angiogenic and osteogenic factors to promote bone formation. This phenotype was partly reversed by inhibiting mTOR. Our study uncovers a surprising dichotomy of ERK pathway functions in osteoblasts, whereby ERK activation promotes the early differentiation of osteoblast precursors, but inhibits the subsequent differentiation of committed osteoblasts via mTOR-mediated regulation of mitochondrial function and SGK1.

molecular biology↗

bioRxiv2021

Heterogeneous Tissue Modulus Improved Prediction of Mechanical Behavior in Osteoporotic Vertebral Cancellous Bone

The structural integrity of cancellous bone, which is essential to its skeletal load-bearing capacity, is governed chiefly by apparent density, trabecular architecture, and tissue material properties. Metabolic bone disorders such as osteoporosis can affect each of these factors, resulting in compromised load-bearing function and fracture. While the impact of apparent density and architecture on bone structural behavior is well-documented, much less is known about the influence of tissue material properties, particularly in osteoporotic bone. In this work, we isolated the influence of tissue modulus on normal and osteoporotic cancellous bone structural integrity, indicated by the apparent elastic modulus under uniaxial compression and patterns of internal tissue strain. Finite element (FE) models derived from 3D micro-computed tomography images were compared to physical testing data of the same samples. Three sets of FE models with increasing material detail were studied: 1) universal tissue elastic modulus (20 GPa), 2) specimen-specific average tissue modulus, and 3) heterogeneous tissue modulus. Applying a universal modulus resulted in overestimation of osteoporotic bone apparent modulus; applying specimen-specific material properties, either as a single average tissue modulus or heterogeneous distribution of tissue moduli, prevented significant apparent modulus overestimation. The greatest improvement in apparent modulus prediction resulted from incorporating a specimen-specific average tissue modulus, though using a specimen-specific heterogeneous tissue modulus provided the most reliable prediction of apparent modulus overall. In addition, median element strain in heterogeneous models also trended lower than in homogeneous models. This finding suggests that heterogeneous material properties may play a role in protective strain-concentrating mechanisms observed in cancellous bone. We conclude that future work exploring trabecular bone mechanics through finite element analysis should incorporate specimen-specific average tissue modulus at a minimum, but heterogeneous tissue modulus is recommended to maximize the functional similarity of bone in silico with bone in vivo.

bioengineering↗

bioRxiv2020

T cells Mediate Progression of Load-Induced Osteoarthritis

Osteoarthritis (OA) is a degenerative disease that manifests as joint damage and synovial inflammation. To date, most studies have focused on the decrease in cartilage stiffness, chondrocyte viability, and changes in matrix-degrading enzymes. With the exception of a few inflammatory cytokines and macrophages, the immune response in OA is poorly characterized, and the crosstalk of joint damage with T and B cells in local lymph nodes is unknown. Here, using an in vivo mouse model of mechanical loading of mouse tibia, we demonstrate that CD8+ T cells and subsets of CD4+ T cells, and not B cells, increase in the local lymph nodes and contribute to the progression of load-induced OA pathology. We demonstrate that T cell response is sex- and age-dependent. Mechanical loading of T cell knock-out mice that lack {beta} T cell receptor carrying cells resulted in attenuation of both cartilage degradation and osteophyte formation in loaded joints, with a concomitant increase in {gamma}{delta}+ T cells. Restricting the migration of T cells in lymphoid tissues through the systemic treatment using Sphingosine-1-phosphate (S1P) inhibitor, decreased localization of T cells in synovium, and attenuated cartilage degradation. Our results lay the foundation of the role T cells play in the joint damage of load-induced OA and allude to the use of S1P inhibitors and T cell immunotherapies for slowing the progression of OA pathology.

immunology↗