It May Seem Inflammatory,but Some T Cells Are Innately Healing to the Bone

Among the most significant developments to have taken place in osteology over the last few decades is an evolution from treating and viewing bone disorders primarily through an endocrine lens to instead seeing them as metabolic disorders that interface at the molecular and cellular level with the immune system. Osteoimmunology was officially born in response to accumulating evidence that the immune system is integrally involved in bone remodeling, but much of the early work focused on the role of conventional αβ T cells in driving bone loss. There is, however, emerging data indicating that innate lymphocytes, in particular γδ T cells, may in fact be important for bone regeneration. We first observed that bisphosphonate‐associated osteonecrosis of the jaw (ONJ), a rare but serious adverse drug effect characterized by nonhealing necrotic bone tissue of the mandible or maxilla, was linked to a deficiency in a subset of γδ T cells found in human peripheral blood. Patients who developed ONJ while on bisphosphonate therapy not only lacked the main subset of circulating γδ T cells, but they also all had underlying conditions that compromised their immune integrity. A number of recent studies have unraveled the role of γδ T cells (and lymphocytes sharing their characteristics) in bone regeneration—particularly for fracture healing. These findings seem to contradict the prevailing view of such “inflammatory” T cells as being bone degenerative rather than restorative. This viewpoint melds together the emerging evidence of these so‐called inflammatory T cells in bone remodeling and healing—showing that they are not in fact “all bad to the bone.” © 2016 American Society for Bone and Mineral Research.     

Tissue responses to thermally-responsive hydrogel nanoparticles

—Thermally-responsive hydrogel nanoparticles of poly(N-isopropylacrylamide) (PNIPAM) and hydroxypropyl cellulose (HPC) have been synthesized. The particle size has been correlated to surfactant concentration and polymer concentration using dynamic laser light scattering techniques. The tissue compatibility of these hydrogel nanoparticles has been evaluated by comparing with poly-L-lactic acid and polystyrene nanoparticles using a mouse implantation model. Our results suggested that both PNIPAM and HPC nanoparticles triggered lesser inflammatory and fibrotic responses among all nanoparticles tested. It is likely that these hydrogel nanoparticles may be suitable for tissue augmentation or drug-delivery devices.     

Mast Cells Trigger Disturbed Bone Healing in Osteoporotic Mice

Mast cells are important tissue-resident sensor and effector immune cells but also play a major role in osteoporosis development. Mast cells are increased in numbers in the bone marrow of postmenopausal osteoporotic patients, and mast cell–deficient mice are protected from ovariectomy (OVX)-induced bone loss. In this study, we showed that mast cell–deficient Mcpt5-Cre R-DTA mice were protected from OVX-induced disturbed fracture healing, indicating a critical role for mast cells in the pathomechanisms of impaired bone repair under estrogen-deficient conditions. We revealed that mast cells trigger the fracture-induced inflammatory response by releasing inflammatory mediators, including interleukin-6, midkine (Mdk), and C-X-C motif chemokine ligand 10 (CXCL10), and promote neutrophil infiltration into the fracture site in OVX mice. Furthermore, mast cells were responsible for reduced osteoblast and increased osteoclast activities in OVX mice callus, as well as increased receptor activator of NF-κB ligand serum levels in OVX mice. Additional in vitro studies with human cells showed that mast cells stimulate osteoclastogenesis by releasing the osteoclastogenic mediators Mdk and CXCL10 in an estrogen-dependent manner, which was mediated via the estrogen receptor alpha on mast cells. In conclusion, mast cells negatively affect the healing of bone fractures under estrogen-deficient conditions. Hence, targeting mast cells might provide a therapeutic strategy to improve disturbed bone repair in postmenopausal osteoporosis. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Effect of Surgically-Induced Weight Loss on Leukocyte Indicators of Chronic Inflammation in Morbid Obesity

Background: Recent evidence suggests that morbid obesity is a chronic inflammatory condition that may be associated with immune dysfunction.To test this hypothesis, we investigated several leukocyte cell surface markers of chronic inflammation and followed their response to surgically-induced weight loss. Methods: 26 patients having Roux-en-Y gastric bypass (RYGBP) for morbid obesity (BMI>40) were compared to 10 normal controls (BMI<25). Relative monocyte and neutrophil frequencies and expression of the activation antigens CD11b (adhesion molecule), CD16 (Fc receptor), and CD62L (Lselectin), were evaluated by flow cytometry preoperatively and at 1, 3, 6 and 12 months after RYGBP. Cases served as their own controls but were also compared to non-obese controls. The results were statistically analyzed using Student's t-test and ANOVA for parametric values and Mann-Whitney along with Kruskal-Wallis ANOVA for nonparametric values Results: The control group had mean age 37 ± 7.6 with mean 23 ± 2.5 and no comorbidities. The mean age of the sample group was 40.36 ± 13.7 with mean BMI 52 ± 8.2. The neutrophil and monocyte relative frequencies of CD11b (monocytes and neutrophils), and CD16 (neutrophils only) were comparable to controls at baseline and did not change significantly with weight loss throughout the study period. However, a significant reduction of CD62L (Lselectin) expression was noted in monocytes and neutrophils at baseline (neutrophils 103 vs 240 gmf, p<0.001) (monocytes104 vs 246 gmf, P<0.001) when compared to normal controls. Levels of L-selectin normalized by 6 months in both monocytes and neutrophils, and by 12 months had become abnormally elevated in monocytes (monocytes 391 gmf, P=0.007); in neutrophils, there was an upward trend that did not reach significance.The expression of the LPS receptor CD14 in the study group was elevated significantly compared to controls at baseline (1129 vs 719 gmf, P=0.004); this marker appeared to return to normal by 3 months. Monocyte CD14+/CD16+ subset percentage were also elevated significantly at baseline (14.3% vs 5.25%, P <0.001), declined throughout the time period but was still significant at 1 year (8.8%, P<0.001). Eosinophil percentages were elevated at baseline (3.3% obese vs 1.8% controls, P=0.003) and remained so throughout the time period. Conclusion: Deficiencies in the immune system of morbidly obese individuals include elevated levels of eosinophils, monocyte CD14, and monocyte CD14+/CD16+ subsets, with depression of monocyte and neutrophil CD62L. These abnormal levels reverse rapidly with surgically-induced weight loss. RYGBP is not only a weight loss operation but also appears to be an immune restorative procedure.     

Anti-inflammatory therapy with a COX-2 inhibitor in Tourette’s syndrome

An infectious/inflammatory process plays a role in at least a subgroup of patients with tics and Tourettes syndrome (TS). Successful antibiotic therapy and prophylaxis was described repeatedly. We report the case of a patient suffering from chronic TS who was treated with celecoxib additionally to the antibiotic prophylaxis. This treatment was associated with a continous improvement of tics and disturbed behaviour, such as aggression and social withdrawal. The withdrawal of celecoxib led to a marked deterioration in TS symptoms while the re-exposition had advantageous therapeutic effects. This result of the treatment with a COX-2 inhibitor supports the view that COX-2 inhibitors show therapeutic benefit in patients suffering from psychiatric disorders in which an inflammatory process is involved in the pathophysiology.     

Regulation of bone lysis in inflammatory diseases

Focal bone erosion is a major pathological feature of several common inflammatory diseases. Over the past decade there have been major advances in our understanding of the factors that regulate osteoclast formation and activity. It is now apparent that receptor activator for NFB (RANK), its ligand RANKL (also known as TRANCE, osteoclast differentiation factor and osteoprotegerin (OPG) ligand) and the RANKL inhibitor OPG, are the major factors regulating osteoclast formation. These molecules influence normal bone physiology and now there is growing evidence that RANK-RANKL interactions also regulate osteoclast formation in disease. This paper reviews recent findings showing expression of RANK, RANKL and OPG in inflammatory diseases including rheumatoid arthritis, periodontal disease and peri-implant loosening. It is emerging that OPG and RANKL are key molecules regulating bone loss in disease and therapeutic intervention that targets these molecules may be helpful in treating a wide range of diseases.     

Cryotherapy and inflammation: evidence beyond the cardinal signs

Abstract

Background: Cryotherapy is one of the most popular electro-physical agents used to 'treat' acute inflammation after a soft tissue injury. Much of the clinical rationale for this is based on anecdotal reports, with most clinicians accepting that cryotherapy has an 'anti' inflammatory effect after injury. There have been a number of recent advances towards improving our understanding of the inflammatory process after soft tissue injury.

Objectives: To review the rationale for cryotherapy intervention in the acute phases of soft tissue injury, whilst considering physiological, cellular and molecular models of inflammation.

Methods: Qualitative review of recent evidence.

Results: Research is restricted to animal models, applying various forms of cryotherapy after induced soft tissue injury. Outcomes focus on the effect that cooling has on key physiological, biochemical and molecular inflammatory events including: secondary cell death, white blood cell behaviour, apoptosis, blood flow and oedema formation.

Conclusion: Cryotherapy can have an influence on key inflammatory events at a cellular and physiological level after an acute soft tissue injury. However, the relative benefits of these effects have yet to be fully elucidated and it is difficult to contextualize within a human model. It is important to continue to update our rationale for applying common electro-physical agents such as cryotherapy after acute soft tissue injury, based on contemporary models of inflammation.     

络得舒方的抗炎机理探讨

本文探讨了络得舒方的抗炎机理。实验结果,络得舒方对摘除肾上腺大鼠甲醛性足肿胀仍有明显抑制作用(P<0.05～0.01);对正常大鼠肾上腺内VitC含量无明显影响(P>0.05);对热诱导所致红细胞溶解有明显抑制作用(P<0.01);对妊娠大鼠离体子宫的自发性收缩有明显抑制作用(P<0.01);对二磷酸腺苷所致的血小板聚集有明显抑制作用(体内体外用药P值均<0.01)。结果提示:络得舒方的抗炎作用不是主要依赖垂体——肾上腺皮质系统,可能与保护红细胞膜、抑制前列腺素合成酶和/或拮抗前列腺素、抑制血小板聚集有关。