Recent Publications

Front Immunol. 2022 Jan 13;12:801505. eCollection 2021. doi: 10.3389/fimmu.2021.801505.


β2-Adrenoceptor Deficiency Results in Increased Calcified Cartilage Thickness and Subchondral Bone Remodeling in Murine Experimental Osteoarthritis
Gundula Rösch, Dominique Muschter, Shahed Taheri, Karima El Bagdadi, Christoph Dorn, Andrea Meurer, Frank Zaucke, Arndt F Schilling, Susanne Grässel, Rainer H Straub, Zsuzsa Jenei-Lanzl

Purpose: Recent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/- ) mice after surgical OA induction.
Methods: OA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining.
Results: WT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time.
Conclusion: We propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.

Osteoarthritis Cartilage. 2022 Jan 8;S1063-4584(22)00002-4. Online ahead of print. doi: 10.1016/j.joca.2021.12.009.

Posttraumatic osteoarthritis as potential modulator of autonomic nervous system function
Z Jenei-Lanzl, G Pongratz

Osteoarthritis Cartilage. 2021 Dec 2;S1063-4584(21)00979-1. doi: 10.1016/j.joca.2021.11.016.

Sympathectomy aggravates subchondral bone changes during osteoarthritis progression in mice without affecting cartilage degeneration or synovial inflammation
Gundula Rösch, Karima El Bagdadi, Dominique Muschter, Shahed Taheri, Christoph Dorn, Andrea Meurer, Rainer H Straub, Frank Zaucke, Arndt F Schilling, Susanne Grässel, Zsuzsa Jenei-Lanzl


Objective: Osteoarthritis (OA) pathogenesis involves the interaction of articular cartilage with surrounding tissues, which are innervated by tyrosine hydroxylase-positive (TH+) sympathetic nerve fibers suggesting a role of the sympathetic nervous system (SNS) during OA progression. We analyzed the effects of sympathectomy (Syx) in a murine OA model.
Methods: Peripheral Syx was generated by 6-hydroxydopamine (6-OHDA) injections in male C57BL/6 mice. OA was induced in wild-type (WT) and Syx mice by destabilization of the medial meniscus (DMM). TH+ fibers and splenic NE were analyzed to evaluate Syx efficiency. OA progression was examined by OARSI and synovitis scores and micro-CT. Expression of TH, α2A- and β2-adrenergic receptors (AR), and activity of osteoblasts (ALP) and osteoclasts (TRAP) was investigated by stainings.
Results: Syx resulted in synovial TH+ fiber elimination and splenic NE decrease. Cartilage degradation and synovitis after DMM were comparably progressive in both WT and Syx mice. Calcified cartilage (CC) and subchondral bone plate (SCBP) thickness and bone volume fraction (BV/TV) increased in Syx mice due to increased ALP and decreased TRAP activities compared to WT 8 weeks after DMMWT and Syx mice developed osteophytes and meniscal ossicles without any differences between the groups. AR numbers decreased in cartilage but increased in synovium and osteophyte regions after DMM in both WT and Syx mice.
Conclusion: Peripheral dampening of SNS activity aggravated OA-specific cartilage calcification and subchondral bone thickening but did not influence cartilage degradation and synovitis. Therefore, SNS might be an attractive target for the development of novel therapeutic strategies for pathologies of the subchondral bone.

Calcif Tissue Int. 2021 Nov;109(5):510-524. Epub 2021 May 22. doi: 10.1007/s00223-021-00864-x.

Investigating the Microchannel Architectures Inside the Subchondral Bone in Relation to Estimated Hip Reaction Forces on the Human Femoral Head
Shahed Taheri, Takashi Yoshida, Kai O Böker, Robert H Foerster, Lina Jochim, Anna Lena Flux, Birgit Grosskopf, Wolfgang Lehmann, Arndt Friedrich Schilling

Abstract: The interplay between articular cartilage (AC) and subchondral bone (SB) plays a pivotal role in cartilage homeostasis and functionality. As direct connective pathways between the two are poorly understood, we examined the location-dependent characteristics of the 3D microchannel network within the SB that connects the basal cartilage layer to the bone marrow (i.e. cartilage-bone marrow microchannel connectors; CMMC). 43 measuring points were defined on five human cadaveric femoral heads with no signs of osteoarthritis (OA) (age ≤ 60), and cartilage-bone cylinders with diameters of 2.00 mm were extracted for high-resolution scanning (n = 215). The micro-CT data were categorized into three groups (load-bearing region: LBR, n = 60; non-load-bearing region: NLBR, n = 60; and the peripheral rim: PR, n = 95) based on a gait analysis estimation of the joint reaction force (young, healthy cohort with no signs of OA). At the AC-SB interface, the number of CMMC in the LBR was 1.8 times and 2.2 times higher compared to the NLBR, and the PR, respectively. On the other hand, the median Feret size of the CMMC were smallest in the LBR (55.2 µm) and increased in the NLBR (73.5 µm; p = 0.043) and the PR (89.1 µm; p = 0.043). AC thickness was positively associated with SB thickness (Pearson's r = 0.48; p < 1e-13), CMMC number. (r = 0.46; p < 1e-11), and circularity index (r = 0.61; p < 1e-38). In conclusion, our data suggest that regional differences in the microchannel architecture of SB might reflect regional differences in loading.

Int J Mol Sci. 2021 Sep 13;22(18):9887. doi: 10.3390/ijms22189887.

The Interaction between microRNAs and the Wnt/β-Catenin Signaling Pathway in Osteoarthritis
Xiaobin Shang, Kai Oliver Böker, Shahed Taheri, Thelonius Hawellek, Wolfgang Lehmann, Arndt F Schilling

Abstract: Osteoarthritis (OA) is a chronic disease affecting the whole joint, which still lacks a disease-modifying treatment. This suggests an incomplete understanding of underlying molecular mechanisms. The Wnt/β-catenin pathway is involved in different pathophysiological processes of OA. Interestingly, both excessive stimulation and suppression of this pathway can contribute to the pathogenesis of OA. microRNAs have been shown to regulate different cellular processes in different diseases, including the metabolic activity of chondrocytes and osteocytes. To bridge these findings, here we attempt to give a conclusive overview of microRNA regulation of the Wnt/β-catenin pathway in bone and cartilage, which may provide insights to advance the development of miRNA-based therapeutics for OA treatment.

Int J Mol Sci. 2021 Aug 19;22(16):8956. doi: 10.3390/ijms22168956.


Anti-Inflammatory Effects of Endogenously Released Adenosine in Synovial Cells of Osteoarthritis and Rheumatoid Arthritis Patients
Rebecca Sohn, Marius Junker, Andrea Meurer, Frank Zaucke, Rainer H Straub, Zsuzsa Jenei-Lanzl


Abstract: Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.

Int J Mol Sci 2021 Apr 2;22(7):3726. doi: 10.3390/ijms22073726.

Heparan Sulfate Deficiency in Cartilage: Enhanced BMP-Sensitivity, Proteoglycan Production and an Anti-Apoptotic Expression Signature after Loading
Matthias Gerstner, Ann-Christine Severmann, Safak Chasan, Andrea Vortkamp, Wiltrud Richter

Abstract: Osteoarthritis (OA) represents one major cause of disability worldwide still evading efficient pharmacological or cellular therapies. Severe degeneration of extracellular cartilage matrix precedes the loss of mobility and disabling pain perception in affected joints. Recent studies showed that a reduced heparan sulfate (HS) content protects cartilage from degradation in OA-animal models of joint destabilization but the underlying mechanisms remained unclear. We aimed to clarify whether low HS-content alters the mechano-response of chondrocytes and to uncover pathways relevant for HS-related chondro-protection in response to loading. Tissue-engineered cartilage with HS-deficiency was generated from rib chondrocytes of mice carrying a hypomorphic allele of Exostosin 1 (Ext1), one of the main HS-synthesizing enzymes, and wildtype (WT) littermate controls. Engineered cartilage matured for 2 weeks was exposed to cyclic unconfined compression in a bioreactor. The molecular loading response was determined by transcriptome profiling, bioinformatic data processing, and qPCR. HS-deficient chondrocytes expressed 3-6% of WT Ext1-mRNA levels. Both groups similarly raised Sox9, Col2a1 and Acan levels during maturation. However, HS-deficient chondrocytes synthesized and deposited 50% more GAG/DNA. TGFβ and FGF2-sensitivity of Ext1gt/gt chondrocytes was similar to WT cells but their response to BMP-stimulation was enhanced. Loading induced similar activation of mechano-sensitive ERK and P38-signaling in WT and HS-reduced chondrocytes. Transcriptome analysis reflected regulation of cell migration as major load-induced biological process with similar stimulation of common (Fosl1, Itgα5, Timp1, and Ngf) as well as novel mechano-regulated genes (Inhba and Dhrs9). Remarkably, only Ext1-hypomorphic cartilage responded to loading by an expression signature of negative regulation of apoptosis with pro-apoptotic Bnip3 being selectively down-regulated. HS-deficiency enhanced BMP-sensitivity, GAG-production and fostered an anti-apoptotic expression signature after loading, all of which may protect cartilage from load-induced erosion.

Cell Signal 2021 Jun;82:109948. Epub 2021 Feb 8. doi: 10.1016/j.cellsig.2021.109948.


Adrenergic signalling in osteoarthritis

Rebecca Sohn, Gundula Rösch, Marius Junker, Andrea Meurer, Frank Zaucke, Zsuzsa Jenei-Lanzl


Abstract: Adrenoceptors (ARs) mediate the effects of the sympathetic neurotransmitters norepinephrine (NE) and epinephrine (E) in the human body and play a central role in physiologic and pathologic processes. Therefore, ARs have long been recognized as targets for therapeutic agents, especially in the field of cardiovascular medicine. During the past decades, the contribution of the sympathetic nervous system (SNS) and particularly of its major peripheral catecholamine NE to the pathogenesis of osteoarthritis (OA) attracted growing interest. OA is the most common degenerative joint disorder worldwide and a disease of the whole joint. It is characterized by progressive degradation of articular cartilage, synovial inflammation, osteophyte formation, and subchondral bone sclerosis mostly resulting in chronic pain. The subchondral bone marrow, the periosteum, the synovium, the vascular meniscus and numerous tendons and ligaments are innervated by tyrosine hydroxylase-positive (TH+) sympathetic nerve fibers that release NE into the synovial fluid and cells of all abovementioned joint tissues express at least one out of nine AR subtypes. During the past decades, several in vitro studies explored the AR-mediated effects of NE on different cell types in the joint. So far, only a few studies used animal OA models to investigate the contribution of distinct AR subtypes to OA pathogenesis in vivo. This narrative review shortly summarizes the current background knowledge about ARs and their signalling pathways at first. In the second part, we focus on recent findings in the field of NE-induced AR-mediated signalling in different joint tissues during OA pathogenesis and at the end, we will delineate the potential of targeting the adrenergic signalling for OA prevention or treatment. We used the PubMed bibliographic database to search for keywords such as 'joint' or 'cartilage' or 'synovium' or 'bone' and 'osteoarthritis' and/or 'trauma' and 'sympathetic nerve fibers' and/or 'norepinephrine' and 'adrenergic receptors / adrenoceptors' as well as 'adrenergic therapy'.

Cells 2021 Feb 1;10(2):298. doi: 10.3390/cells10020298.


Mechanical Stress Induce PG-E2 in Murine Synovial Fibroblasts Originating from the Temporomandibular Joint

Ute Nazet, Laura Feulner, Dominique Muschter, Patrick Neubert, Valentin Schatz, Susanne Grässel, Jonathan Jantsch, Peter Proff, Agnes Schröder, Christian Kirschneck


Abstract: Genetic predisposition, traumatic events, or excessive mechanical exposure provoke arthritic changes in the temporomandibular joint (TMJ). We analysed the impact of mechanical stress that might be involved in the development and progression of TMJ osteoarthritis (OA) on murine synovial fibroblasts (SFs) of temporomandibular origin. SFs were subjected to different protocols of mechanical stress, either to a high-frequency tensile strain for 4 h or to a tensile strain of varying magnitude for 48 h. The TMJ OA induction was evaluated based on the gene and protein secretion of inflammatory factors (Icam-1, Cxcl-1, Cxcl-2, Il-1ß, Il-1ra, Il-6, Ptgs-2, PG-E2), subchondral bone remodelling (Rankl, Opg), and extracellular matrix components (Col1a2, Has-1, collagen and hyaluronic acid deposition) using RT-qPCR, ELISA, and HPLC. A short high-frequency tensile strain had only minor effects on inflammatory factors and no effects on the subchondral bone remodelling induction or matrix constituent production. A prolonged tensile strain of moderate and advanced magnitude increased the expression of inflammatory factors. An advanced tensile strain enhanced the Ptgs-2 and PG-E2 expression, while the expression of further inflammatory factors were decreased. The tensile strain protocols had no effects on the RANKL/OPG expression, while the advanced tensile strain significantly reduced the deposition of matrix constituent contents of collagen and hyaluronic acid. The data indicates that the application of prolonged advanced mechanical stress on SFs promote PG-E2 protein secretion, while the deposition of extracellular matrix components is decreased.

Osteologie 2020, doi: 10.1055/a-1206-6663.


Knorpel-Knochenmark-Mikro-Konnektoren im subchondralen Knochen

Shahed Taheri, Kai O. Böker, Wolfgang Lehmann, Arndt Friedrich Schilling


Abstract: The interaction of the subchondral bone with the articular cartilage is of fundamental importance for joint physiology. Studies on animal and human models have suggested that the lower margin of the articular cartilage is connected to the medullary cavity via small defects or microchannels. While these cartilage-bone marrow micro-connectors (CMMC) can potentially be crucial for molecular exchange, bone-cartilage crosstalk, and even cartilage nutrition, the current knowledge regarding them is limited and incoherent. This review summarizes the so far described characteristics of this anatomical feature in different species, explores recurring patterns in the literature, and discusses its potential functionality.

Int J Mol Sci 2020 May 30;21(11):3924. doi: 10.3390/ijms21113924.


Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via β2-Adrenoceptor-Mediated ERK1/2 and PKA Phosphorylation

Jessica Hedderich, Karima El Bagdadi, Peter Angele, Susanne Grässel, Andrea Meurer, Rainer H Straub, Frank Zaucke, Zsuzsa Jenei-Lanzl


Abstract: Bone marrow-derived mesenchymal stem cells (BMSCs) represent an alternative to chondrocytes to support cartilage regeneration in osteoarthritis (OA). The sympathetic neurotransmitter norepinephrine (NE) has been shown to inhibit their chondrogenic potential; however, their proliferation capacity under NE influence has not been studied yet. Therefore, we used BMSCs obtained from trauma and OA donors and compared the expression of adrenergic receptors (AR). Then, BMSCs from both donor groups were treated with NE, as well as with combinations of NE and α1-, α2- or β1/2-AR antagonists (doxazosin, yohimbine or propranolol). Activation of AR-coupled signaling was investigated by analyzing ERK1/2 and protein kinase A (PKA) phosphorylation. A similar but not identical subset of ARs was expressed in trauma (α2B-, α2C- and β2-AR) and OA BMSCs (α2A-, α2B-, and β2-AR). NE in high concentrations inhibited the proliferation of both trauma and OA BMCSs significantly. NE in low concentrations did not influence proliferation. ERK1/2 as well as PKA were activated after NE treatment in both BMSC types. These effects were abolished only by propranolol. Our results demonstrate that NE inhibits the proliferation and accordingly lowers the regenerative capacity of human BMSCs likely via β2-AR-mediated ERK1/2 and PKA phosphorylation. Therefore, targeting β2-AR-signaling might provide novel OA therapeutic options.

F1000Res 2020 May 4;9:F1000 Faculty Rev-325. eCollection 2020. doi: 10.12688/f1000research.22115.1.


Recent advances in the treatment of osteoarthritis

Susanne Grässel, Dominique Muschter


Abstract: Osteoarthritis (OA) is one of the most debilitating diseases and is associated with a high personal and socioeconomic burden. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects. Efforts to identify more tailored treatment options led to the development of strategies that enabled the classification of patient subgroups from the pool of heterogeneous phenotypes that display distinct common characteristics. To this end, the classification differentiates the structural endotypes into cartilage and bone subtypes, which are predominantly driven by structure-related degenerative events. In addition, further classifications have highlighted individuals with an increased inflammatory contribution (inflammatory phenotype) and pain-driven phenotypes as well as senescence and metabolic syndrome phenotypes. Most probably, it will not be possible to classify individuals by a single definite subtype, but it might help to identify groups of patients with a predominant pathology that would more likely benefit from a specific drug or cell-based therapy. Current clinical trials addressed mainly regeneration/repair of cartilage and bone defects or targeted pro-inflammatory mediators by intra-articular injections of drugs and antibodies. Pain was treated mostly by antagonizing nerve growth factor (NGF) activity and its receptor tropomyosin-related kinase A (TrkA). Therapies targeting metabolic disorders such as diabetes mellitus and senescence/aging-related pathologies are not specifically addressing OA. However, none of these therapies has been proven to modify disease progression significantly or successfully prevent final joint replacement in the advanced disease stage. Within this review, we discuss the recent advances in phenotype-specific treatment options and evaluate their applicability for use in personalized OA therapy.

Int J Mol Sci. 2020 Mar 18;21(6):2085. doi: 10.3390/ijms21062085.

Adrenoceptor Expression during Intervertebral Disc Degeneration
Johannes Kupka, Annika Kohler, Karima El Bagdadi, Richard Bostelmann, Marco Brenneis, Christoph Fleege, Danny Chan, Frank Zaucke, Andrea Meurer, Marcus Rickert, Zsuzsa Jenei-Lanzl

Abstract: Healthy and degenerating intervertebral discs (IVDs) are innervated by sympathetic nerves, however, adrenoceptor (AR) expression and functionality have never been investigated systematically. Therefore, AR gene expression was analyzed in both tissue and isolated cells from degenerated human IVDs. Furthermore, human IVD samples and spine sections of wildtype mice (WT) and of a mouse line that develops spontaneous IVD degeneration (IVDD, in SM/J mice) were stained for ARs and extracellular matrix (ECM) components. In IVD homogenates and cells α1a-, α1b-, α2a-, α2b-, α2c-, β1-, and β2-AR genes were expressed. In human sections, β2-AR was detectable, and its localization parallels with ECM alterations. Similarly, in IVDs of WT mice, only β2-AR was expressed, and in IVDs of SM/J mice, β2AR expression was stronger accompanied by increased collagen II, collagen XII, decorin as well as decreased cartilage oligomeric matrix protein expression. In addition, norepinephrine stimulation of isolated human IVD cells induced intracellular signaling via ERK1/2 and PKA. For the first time, the existence and functionality of ARs were demonstrated in IVD tissue samples, suggesting that the sympathicus might play a role in IVDD. Further studies will address relevant cellular mechanisms and thereby help to develop novel therapeutic options for IVDD.

Am J Sports Med. 2020 Mar;48(3):612-623. Epub 2020 Jan 31. doi: 10.1177/0363546519899087.

Integrin α10β1-Selected Mesenchymal Stem Cells Mitigate the Progression of Osteoarthritis in an Equine Talar Impact Model
Michelle L Delco, Margaret Goodale, Jan F Talts, Sarah L Pownder, Matthew F Koff, Andrew D Miller, Bridgette Nixon, Lawrence J Bonassar, Evy Lundgren-Åkerlund, Lisa A Fortier

Background: Early intervention with mesenchymal stem cells (MSCs) after articular trauma has the potential to limit progression of focal lesions and prevent ongoing cartilage degeneration by modulating the joint environment and/or contributing to repair. Integrin α10β1 is the main collagen type II binding receptor on chondrocytes, and MSCs that are selected for high expression of the α10 subunit have improved chondrogenic potential. The ability of α10β1-selected (integrin α10high) MSCs to protect cartilage after injury has not been investigated.

Purpose: To investigate integrin α10high MSCs to prevent posttraumatic osteoarthritis in an equine model of impact-induced talar injury.

Study design: Controlled laboratory study.

Methods: Focal cartilage injuries were created on the tali of horses (2-5 years, n = 8) by using an impacting device equipped to measure impact stress. Joints were treated with 20 × 106 allogenic adipose-derived α10high MSCs or saline vehicle (control) 4 days after injury. Synovial fluid was collected serially and analyzed for protein content, cell counts, markers of inflammation (prostaglandin E2, tumor necrosis factor α) and collagen homeostasis (procollagen II C-propeptide, collagen type II cleavage product), and glycosaminoglycan content. Second-look arthroscopy was performed at 6 weeks, and horses were euthanized at 6 months. Joints were imaged with radiographs and quantitative 3-T magnetic resonance imaging. Postmortem examinations were performed, and India ink was applied to the talar articular surface to identify areas of cartilage fibrillation. Synovial membrane and osteochondral histology was performed, and immunohistochemistry was used to assess type I and II collagen and lubricin. A mixed effect model with Tukey post hoc and linear contrasts or paired t tests were used, as appropriate.

Results: Integrin α10high MSC-treated joints had less subchondral bone sclerosis on radiographs (P = .04) and histology (P = .006) and less cartilage fibrillation (P = .04) as compared with control joints. On gross pathology, less India ink adhered to impact sites in treated joints than in controls, which may be explained by the finding of more prominent lubricin immunostaining in treated joints. Prostaglandin E2 concentration in synovial fluid and mononuclear cell synovial infiltrate were increased in treated joints, suggesting possible immunomodulation by integrin α10high MSCs.

Conclusion: Intra-articular administration of integrin α10high MSCs is safe, and evidence suggests that the cells mitigate the effects of joint trauma.

Clinical relevance: This preclinical study indicates that intra-articular therapy with integrin α10high MSCs after joint trauma may be protective against posttraumatic osteoarthritis.

Bone 2020 Apr;133:115181. Epub 2020 Jan 8. doi: 10.1016/j.bone.2019.115181.

Sensory neuropeptides are required for bone and cartilage homeostasis in a murine destabilization-induced osteoarthritis model
Dominique Muschter, Lutz Fleischhauer, Shahed Taheri, Arndt F Schilling, Hauke Clausen-Schaumann, Susanne Grässel

Abstract: Numerous studies identified a role for the sensory neuropeptides substance P (SP) and alpha calcitonin gene-related peptide (αCGRP) in osteoarthritis (OA) pain behavior. Surprisingly, little attention has been paid on how their trophic effects on cartilage and bone cells might affect structural changes of bone and cartilage in OA pathology. Here, we sought to elucidate sensory neuropeptides influence on structural alterations of bone and cartilage during murine OA pathophysiology. OA was induced by destabilization of the medial meniscus (DMM) in the right knee joint of 12 weeks old male C57Bl/6J wildtype (WT) mice and mice either deficient for SP (tachykinin 1 (Tac1)-/-) or αCGRP. By OARSI histopathological grading we observed significant cartilage matrix degradation after DMM surgery in αCGRP-deficient mice after 4 weeks whereas Tac1-/- scores were not different to sham mice before 12 weeks after surgery. Indentation-type atomic force microscopy (IT-AFM) identified a strong superficial zone (SZ) cartilage phenotype in Tac1-/- Sham mice. Opposed to WT and αCGRP-/- mice, SZ cartilage of Tac1-/- mice softened 2 weeks after OA induction. In Tac1-/- DMM mice, bone volume to total volume ratio (BV/TV) increased significantly compared to the Tac1-/- Sham group, 2 weeks after surgery. WT mice had reduced BV/TV compared to αCGRP-/- and Tac1-/- mice after 12 weeks. Increased calcified cartilage thickness and medial condyle diameter were detected in the medial tibia of all groups 8 weeks after OA induction by nanoCT analysis. Meniscal ossification occurred in all OA groups, but was significantly stronger in the absence of neuropeptides. Increased serum concentration of the respective non-deleted neuropeptide was observed in both neuropeptide-deficient mice strains. Both neuropeptides protect from age-related bone structural changes under physiological conditions and SP additionally demonstrates an anabolic effect on bone structure preservation in a pathophysiological situation. Both neuropeptide deficient mice display an intrinsic structural cartilage matrix phenotype that might alter progression of cartilage degeneration in OA.