2019


Int J Mol Sci. 2019 Feb 12;20(3). pii: E770. doi: 10.3390/ijms20030770.

Developmental Transformation and Reduction of 3 Connective Cavities within the Subchondral Bone.

 

Shahed Taheri*1 , Thomas Winkler*2 , Lia Sabrina Schenk*2 , Carl Neuerburg3 4 , Sebastian Felix Baumbach3 , Jozef Zustin4 , Wolfgang Lehmann1 5 , Arndt Friedrich Schilling1 

(SP5)

 

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Abstract

It is widely accepted that the subchondral bone (SCB) plays a crucial role in the 15 physiopathology of osteoarthritis (OA), although its contribution is still debated. Much of the pre16 clinical research on the role of SCB is concentrated on comparative evaluations of healthy vs. early 17 OA or early OA vs. advanced OA cases, while neglecting how pure maturation could change the 18 SCB’s microstructure. To assess the transformations of the healthy SCB from young age to early 19 adulthood, we examined the microstructure and material composition of the medial condyle of the 20 femur in calves (3 months) and cattle (18 months) for the calcified cartilage (CC) and the 21 subchondral bone plate (SCBP). The entire subchondral zone (SCZ) was significantly thicker in 22 cattle compared to calves, although the proportion of the CC and SCBP thicknesses were relatively 23 constant. The trabecular number (Tb.N.) and the connectivity density (Conn.D) was significantly 24 higher in the deeper region of the SCZ, while the bone volume fraction (BV/TV), and the degree of 25 anisotropy (DA) were more affected by age rather than the region. The mineralization increased 26 within the first 250 µm of the SCZ irrespective of sample type, and became stable thereafter. Cattle 27 exhibited higher mineralization than calves at all depths, with a mean Ca/P ratio of 1.59 and 1.64 for 28 calves and cattle, respectively. Collectively, these results indicate that the SCZ is highly dynamic at 29 early age, and CC is the most dynamic layer of the SCZ. 

 

Keywords

Bone histomorphometry; Subchondral bone; Microcomputed tomography; 31 Osteoarthritis; Calcified cartilage 

 

 

 


Annals of Stem Cell Research 

Integrin α10β1-selected Equine MSCs have Improved Chondrogenic Differentiation, Immunomodulatory and Cartilage Adhesion Capacity.  

 

Kristina Uvebrant, Linda Reimer Rasmusson, Jan F. Talts, Paolo Alberton, Attila Aszodi and Evy Lundgren-Äkerlund.

(SP1)

 

 

 



2018



Int J Mol Sci. 2018 Jan 26; 19 (2). pii: E367. doi: 10.3390/ijms19020367.

Do Neuroendocrine Peptides and Their Receptors Qualify as Novel Therapeutic Targets in Osteoarthritis?

 

Grässel S1, Muschter D2.

(SP4)

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Int J Mol Sci. 2018 Jan 26; 19 (2). pii: E367. doi: 10.3390/ijms19020367.

Do Neuroendocrine Peptides and Their Receptors Qualify as Novel Therapeutic Targets in Osteoarthritis?

 

Grässel S1, Muschter D2.

(SP4)

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Abstract

Joint tissues like synovium, articular cartilage, meniscus and subchondral bone, are targets for neuropeptides. Resident cells of these tissues express receptors for various neuroendocrine-derived peptides including proopiomelanocortin (POMC)-derived peptides, i.e., α-melanocyte-stimulating hormone (α-MSH), adrenocorticotropin (ACTH) and β-endorphin (β-ED), and sympathetic neuropeptides like vasoactive intestinal peptide (VIP) and neuropeptide y (NPY). Melanocortins attained particular attention due to their immunomodulatory and anti-inflammatory effects in several tissues and organs. In particular, α-MSH, ACTH and specific melanocortin-receptor (MCR) agonists appear to have promising anti-inflammatory actions demonstrated in animal models of experimentally induced arthritis and osteoarthritis (OA). Sympathetic neuropeptides have obtained increasing attention as they have crucial trophic effects that are critical for joint tissue and bone homeostasis. VIP and NPY are implicated in direct and indirect activation of several anabolic signaling pathways in bone and synovial cells. Additionally, pituitary adenylate cyclase-activating polypeptide (PACAP) proved to be chondroprotective and, thus, might be a novel target in OA. Taken together, it appears more and more likely that the anabolic effects of these neuroendocrine peptides or their respective receptor agonists/antagonists may be exploited for the treatment of patients with inflammatory and degenerative joint diseases in the future.

KEYWORDS

NPY; PACAP; VIP; alpha-MSH; neuroendocrine; osteoarthritis; proopiomelanocortin

PMID: 29373492

 

 

 

 


Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):851-859. doi: 10.1016/j.bbadis.2017.12.024. Epub 2017 Dec 19.

Extracellular matrix content and WNT/β-catenin levels of cartilage determine the chondrocyte response to compressive load.

 

Praxenthaler H1, Krämer E1, Weisser M1, Hecht N1, Fischer J1, Grossner T2, Richter W3.

(SP3)


Abstract

During osteoarthritis (OA)-development extracellular matrix (ECM) molecules are lost from cartilage, thus changing gene-expression, matrix synthesis and biomechanical competence of the tissue. Mechanical loading is important for the maintenance of articular cartilage; however, the influence of an altered ECM content on the response of chondrocytes to loading is not well understood, but may provide important insights into underlying mechanisms as well as supplying new therapies for OA. Objective here was to explore whether a changing ECM-content of engineered cartilage affects major signaling pathways and how this alters the chondrocyte response to compressive loading. Activity of canonical WNT-, BMP-, TGF-β- and p38-signaling was determined during maturation of human engineered cartilage and followed after exposure to a single dynamic compression-episode. WNT/β-catenin- and pSmad1/5/9-levels declined with increasing ECM-content of cartilage. While loading significantly suppressed proteoglycan-synthesis and ACAN-expression at low ECM-content this catabolic response then shifted to an anabolic reaction at high ECM-content. A positive correlation was observed between GAG-content and load-induced alteration of proteoglycan-synthesis. Induction of high β-catenin levels by the WNT-agonist CHIR suppressed load-induced SOX9- and GAG-stimulation in mature constructs. In contrast, the WNT-antagonist IWP-2 was capable of attenuating load-induced GAG-suppression in immature constructs. In conclusion, either ECM accumulation-associated or pharmacologically induced silencing of WNT-levels allowed for a more anabolic reaction of chondrocytes to physiological loading. This is consistent with the role of proteoglycans in sequestering WNT-ligands in the ECM, thus reducing WNT-activity and also provides a novel explanation of why low WNT-activity in cartilage protects from OA-development in mechanically overstressed cartilage.

Copyright © 2017 Elsevier B.V. All rights reserved.

 

KEYWORDS:

Cell signaling; Chondrocyte; Mechanical loading; Osteoarthritis; SOX9

PMID: 29277327 DOI: 10.1016/j.bbadis.2017.12.024

 

 

 


J Cell Physiol. 2018 Jan;233(1):699-711. doi: 10.1002/jcp.25933. Epub 2017 May 19.

Global chondrocyte gene expression after a single anabolic loading period: Time evolution and re-inducibility of mechano-responses.

 

Scholtes S1, Krämer E1, Weisser M1, Roth W1, Luginbühl R2, Grossner T3, Richter W1. 

(SP3)


Abstract

Aim of this study was a genome-wide identification of mechano-regulated genes and candidate pathways in human chondrocytes subjected to a single anabolic loading episode and characterization of time evolution and re-inducibility of the response. Osteochondral constructs consisting of a chondrocyte-seeded collagen-scaffold connected to β-tricalcium-phosphate were pre-cultured for 35 days and subjected to dynamic compression (25% strain, 1 Hz, 9 × 10 min over 3 hr) before microarray-profiling was performed. Proteoglycan synthesis was determined by 35 S-sulfate-incorporation over 24 hr. Cell viability and hardness of constructs were unaltered by dynamic compression while proteoglycan synthesis was significantly stimulated (1.45-fold, p = 0.016). Among 115 significantly regulated genes, 114 were up-regulated, 48 of them ≥ twofold. AP-1-relevant transcription factors FOSB and FOS strongly increased in line with elevated ERK1/2-phosphorylation and rising MAP3K4 expression. Expression of proteoglycan-synthesizing enzymes CHSY1 and GALNT4 was load-responsive as were factors associated with the MAPK-, TGF-β-, calcium-, retinoic-acid-, Wnt-, and Notch-signaling pathway which were significantly upregulated SOX9, and BMP6 levels rose significantly also after multiple loading episodes at daily intervals even at the 14th cycle with no indication for desensitation. Canonical pSmad2/3 and pSmad1/5/9-signaling showed no consistent regulation. This study associates novel genes with mechanoregulation in chondrocytes, raising SOX9 protein levels with anabolic loading and suggests that more pathways than so far anticipated apparently work together in a complex network of stimulators and feedback-regulators. Upregulation of mechanosensitive indicators extending differentially into the resting time provides crucial knowledge to maximize cartilage matrix deposition for the generation of high-level cartilage replacement tissue.

© 2017 Wiley Periodicals, Inc.

 

KEYWORDS:

BMP signalling; MAPK; SOX9; TGF-β signaling; proteoglycan synthesis

PMID: 28369921 DOI: 10.1002/jcp.25933

 



2017


Int J Mol Sci. 2017 Apr 28; 18 (5). pii: E931. doi: 10.3390/ijms18050931.

Peripheral Nerve Fibers and Their Neurotransmitters in Osteoarthritis Pathology.

 

Grässel S1, Muschter D2.

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Abstract

The importance of the nociceptive nervous system for maintaining tissue homeostasis has been known for some time, and it has also been suggested that organogenesis and tissue repair are under neuronal control. Changes in peripheral joint innervation are supposed to be partly responsible for degenerative alterations in joint tissues which contribute to development of osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin, which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis. They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological and pathophysiological conditions, in addition to their classical neurological features.

KEYWORDS:

CGRP; adrenoceptors; cartilage; neurotransmitters; osteoarthritis; peripheral nervous system; subchondral bone; substance P

PMID: 28452955

PMCID: PMC5454844