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We recently demonstrated that clindamycin exhibits activities in acute and chronic models of pain and inflammation. In the present study, we investigated the effects of clindamycin and a clindamycin acetylated derivative (CAD) in models of acute joint inflammation and in a microbiological assay. Joint inflammation was induced in mice by intraarticular (i.a.) injection of zymosan or lipopolysaccharide (LPS). Clindamycin or CAD were administered via the intraperitoneal route 1 h before zymosan or LPS. Paw withdrawal threshold, joint diameter, histological changes, neutrophil recruitment, tumor necrosis factor-α (TNF-α) production and phosphorylation of the IκBα and NF-κB/p65 were evaluated. In vitro assays were used to measure the antibacterial activity of clindamycin and CAD and also their effects on zymosan-induced TNF-α production by RAW264.7 macrophages. Clindamycin exhibited activity against Staphylococcus aureus and Salmonella Typhimurium ATCC® strains at much lower concentrations than CAD. Intraarticular injection of zymosan or LPS induced articular hyperalgesia, edema and neutrophil infiltration in the joints. Zymosan also induced histological changes, NF-κB activation and TNF-α production. Responses induced by zymosan and LPS were inhibited by clindamycin (200 and 400 mg/kg) or CAD (436 mg/kg). Both clindamycin and CAD inhibited in vitro TNF-α production by macrophages. In summary, we provided additional insights of the clindamycin immunomodulatory effects, whose mechanism was associated with NF-κB inhibition and reduced TNF-α production. Such effects were extended to a clindamycin derivative with reduced antibacterial activity, indicating that clindamycin derivatives should be investigated as candidates to drugs that could be useful in the management of inflammatory and painful conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Nephrotic syndrome (NS) is associated with kidney dysfunction and is an important cause of morbidity and mortality in industrialized countries. Here, we evaluated the effects of the phosphodiesterase-4 (PDE-4) inhibitors rolipram and roflumilast on a doxorubicin-induced NS model. Early-stage rolipram treatment preserved glomerular filtration barrier function, as indicated by reduced serum protein and albumin loss and the prevention of hypercholesterolemia. These effects were associated with reduced glomerular and tubular lesions and abrogated renal cell apoptosis. In addition, rolipram treatment reduced inflammation, which was characterized by a decrease in macrophage accumulation and reduced levels of CCL2 and TNF in the kidneys. Rolipram also reduced renal fibrosis, which was associated with decreased α-smooth muscle actin (α-SMA) area and increased metalloproteinase 9 (MMP9) activity in renal tissue. Late-stage rolipram or roflumilast treatment preserved glomerular filtration barrier function, as characterized by reduced serum albumin loss, decreased proteinuria, and the prevention of hypercholesterolemia. Importantly, only roflumilast treatment was associated with a reduction in glomerular and tubular lesions at this time point. In addition, both rolipram and roflumilast reduced renal tissue fibrosis and MMP9 activity in renal tissue., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: This study aimed to evaluate the involvement of Angiotensin II (Ang II) in joint lesions associated with osteoarthritis (OA) in vitro and in vivo., Methods: Chondrocyte cultures were obtained from knee joints of neonatal rats and stimulated with Ang II/MIA/ACE inhibitors. In vivo, rats treated or not with the ACE inhibitor captopril, received daily injections of Ang II or sodium monoiodoacetate (MIA) in knee joints for evaluation of cartilage, bone, and synovial lesions., Results: Cultured chondrocytes expressed the mRNA for Ace, Agtr1, Agtr2, and Mas1. Stimulating cells with Ang II reduced chondrocyte viability and metabolism. Accordingly, in vivo Ang II injection into the knees of rats triggered hyperalgesia, joint edema, increased the number of leukocytes in the joint cavity, and induced cartilage lesions associated with OA alterations. In further experiments, Ang II synthesis was prevented with the ACE inhibitor Captopril in the context of MIA-induced OA. Ang II inhibition with captopril improved the OARSI score, induced chondroprotection, and reduced the leukocyte recruitment from synovium after MIA. Additionally, captopril prevented MIA-induced bone resorption, by decreasing the number of osteoclasts and increasing the expression of IL-10 in the bone. In vitro, inhibiting Ang II synthesis decreased MIA-induced chondrocyte death and increased Col2a1 transcription., Conclusion: Ang II induces chondrocyte death and joint tissue damages associated with OA and its modulation can be a therapeutic strategy in osteoarthritis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Suppressor of cytokine signaling (SOCS) proteins are significant regulators of cellular immune responses. Therefore, the role of SOCS in bone-inflammatory disorders, including arthritis and periodontitis, has been investigated in experimental and clinical conditions. Recent evidence shows that SOCS proteins are expressed in major bone-related cells, including osteoblasts, osteoclasts, chondrocytes and synoviocytes, although their direct role in these cells is not fully described. These signaling molecules, especially SOCS1, 2 and 3, were shown to play critical roles in the control of bone resorption associated to inflammation. This review focuses on the involvement of SOCS proteins in inflammatory bone remodeling, including their direct and indirect role in the control of osteoclast hyperactivation, during arthritis and periodontitis. The description of the roles of SOCS proteins in inflammatory bone diseases highlights the pathways involved in the pathophysiology of these conditions and, thus, may contribute to the development and improvement of potential therapeutic interventions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The renin-angiotensin system (RAS), aside its classical hormonal properties, has been implicated in the pathogenesis of inflammatory disorders. The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas Receptor (ACE2/Ang-(1-7)/MasR) axis owns anti-inflammatory properties and was recently associated with bone remodeling in osteoporosis. Thus, the aim of this study was to characterize the presence and effects of the ACE2/Ang-(1-7)/MasR axis in osteoblasts and osteoclasts in vitro and in vivo. ACE2 and MasR were detected by qPCR and western blotting in primary osteoblast and osteoclast cell cultures. Cells were incubated with different concentrations of Ang-(1-7), diminazene aceturate (DIZE - an ACE2 activator), A-779 (MasR antagonist) and/or LPS in order to evaluate osteoblast alkaline phosphatase and mineralized matrix, osteoclast differentiation and cytokine expression, and mRNA levels of osteoblasts and osteoclasts markers. An experimental model of alveolar bone resorption triggered by dysbiosis in rats was used to evaluate bone remodeling in vivo. Rats were treated with Ang-(1-7), DIZE and/or A-779 and periodontal samples were collected for immunohistochemistry, morphometric analysis, osteoblast and osteoclast count and cytokine evaluation. Human gingival samples from healthy and periodontitis patients were also evaluated for detection of ACE2 and MasR expression. Osteoblasts and osteoclasts expressed ACE2 and MasR in vitro and in vivo. LPS stimulation or alveolar bone loss induction reduced ACE2 expression. Treatment of bone cells with Ang-(1-7) or DIZE stimulated osteoblast ALP, matrix synthesis, upregulated osterix, osteocalcin and collagen type 1 transcription, reduced IL-6 expression, and decreased osteoclast differentiation, RANK and IL-1β mRNA transcripts, and IL-6 and IL-1β levels, in a MasR-dependent manner. In vivo, Ang-(1-7) and DIZE decreased alveolar bone loss through improvement of osteoblast/osteoclast ratio. A-779 reversed such phenotype. ACE2/Ang-(1-7)/MasR axis activation reduced IL-6 expression, but not IL-1β. ACE2 and MasR were also detected in human gingival samples, with higher expression in the healthy than in the inflamed tissues. These findings show that the ACE2/Ang-(1-7)/MasR is an active player in alveolar bone remodeling., (Copyright © 2019 Elsevier Inc. All rights reserved.)

5-Lipoxygenase (5-LO) metabolites are important pro-inflammatory lipid mediators. However, much still remains to be understood about the role of such mediators in bone remodeling. This study aimed to investigate the effect of 5-LO metabolites, LTB4 and CysLTs, in a model of mechanical loading-induced bone remodeling. Strain-induced tooth movement and consequently alveolar bone resorption/apposition was achieved by using a coil spring placed on molar and attached to incisors of C57BL6 (wild-type-WT), 5-LO deficient mice (5-LO(-/-)) and mice treated with 5-LO inhibitor (zileuton-ZN) or with antagonist of CysLTs receptor (montelukast-MT). The amount of bone resorption and the number of osteoclasts were determined morphometrically. The expression of inflammatory and bone remodeling markers in periodontium was analyzed by qPCR. Osteoclast differentiation and TNF-α production were evaluated in vitro using RAW 264.7 cells treated with LTB4 or LTD4. Bone resorption, TRAP(+) cells and expression of Tnfa, Il10 and Runx2 were significantly diminished in 5-LO(-/-), ZN- and MT-treated mice. The expression of Rank was also reduced in 5-LO(-/-) and MT-treated mice. Accordingly, LTB4 and LTD4 in association with RANKL promoted osteoclast differentiation and increased TNF-α release in vitro. These data demonstrate that the absence of 5-LO metabolites, LTB4 and CysLTs reduces osteoclast recruitment and differentiation, consequently diminishing bone resorption induced by mechanical loading. Thus, 5-LO might be a potential target for controlling bone resorption in physiological and pathological conditions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3., (Copyright © 2012 Elsevier Inc. All rights reserved.)