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).     

Investigation of the in vitro toxicological properties of the synthetic cannabimimetic drug CP-47,497-C8

Cannabicyclohexanol (CP-47,497-C8) is a representative of a group of cannabimimetic cyclohexylphenols which is added to herbal mixtures as a cannabis substitute since 2008. Although in the beginning CP-47,497-C8 was the main ingredient of “Spice” and similar products, it was partly replaced by aminoalkylindole-type cannabinoid receptor agonists like JWH-018, JWH-073 or JWH-250, but never completely disappeared from the market. Since information on its toxicological properties is scarce, we investigated the effects of the drug in human derived cell lines. The cytotoxic effects were studied in a panel of assays (SRB, XTT, LDHe and NR tests) in a buccal derived (TR146) and a liver derived (HepG2) cell line. The strongest effects were seen in the two former assays at levels ≥ 7.5 μM indicating that the compound interferes with protein synthesis and causes membrane damage. In additional comet assays, DNA damage was detected at levels ≥ 10 μM. Experiments with lesion specific enzymes showed that these effects are not due to oxidative damage of DNA bases. The negative findings obtained in Salmonella/microsome assays and the positive results of micronucleus tests with the cell lines indicate that the compound does not cause gene mutations but acts on the chromosomal level. In contrast to other synthetic cannabinoids, no indication for estrogenic/antiestrogenic properties was seen in a luciferase assay with bone marrow derived U2-OS cells. In conclusion, our findings show that the drug has only weak cytotoxic properties. However, the induction of chromosomal damage indicates that it may cause adverse effects in users due to its impact on the stability of the genetic material.     

Existential neuroscience: effects of mortality salience on the neurocognitive processing of attractive opposite-sex faces

Being reminded of the inherently finite nature of human existence has been demonstrated to elicit strivings for sexual reproduction and the formation and maintenance of intimate relationships. Recently, it has been proposed that the perception of potential mating partners is influenced by mortality salience. Using functional magnetic resonance imaging, we investigated the neurocognitive processing of attractive opposite-sex faces after priming with death-related words for heterosexual men and women. Significant modulations of behavioral and neural responses were found when participants were requested to decide whether they would like to meet the presented person. Men were more in favor of meeting attractive women after being primed with death-related words compared to a no-prime condition. Increased neural activation could be found under mortality salience in the left anterior insula and the adjacent lateral prefrontal cortex (lPFC) for both men and women. As previously suggested, we believe that the lPFC activation reflects an approach-motivated defense mechanism to overcome concerns that are induced by being reminded of death and dying. Our results provide insight on a neurocognitive level that approach motivation in general, and mating motivation in particular is modulated by mortality salience.     

Selective increase of in vivo firing frequencies in DA SN neurons after proteasome inhibition in the ventral midbrain

The impairment of protein degradation via the ubiquitin‐proteasome system (UPS) is present in sporadic Parkinson's disease (PD), and might play a key role in selective degeneration of vulnerable dopamine (DA) neurons in the substantia nigra pars compacta (SN). Further evidence for a causal role of dysfunctional UPS in familial PD comes from mutations in parkin, which results in a loss of function of an E3‐ubiquitin‐ligase. In a mouse model, genetic inactivation of an essential component of the 26S proteasome lead to widespread neuronal degeneration including DA midbrain neurons and the formation of alpha‐synuclein‐positive inclusion bodies, another hallmark of PD. Studies using pharmacological UPS inhibition in vivo had more mixed results, varying from extensive degeneration to no loss of DA SN neurons. However, it is currently unknown whether UPS impairment will affect the neurophysiological functions of DA midbrain neurons. To answer this question, we infused a selective proteasome inhibitor into the ventral midbrain in vivo and recorded single DA midbrain neurons 2 weeks after the proteasome challenge. We found a selective increase in the mean in vivo firing frequencies of identified DA SN neurons in anesthetized mice, while those in the ventral tegmental area (VTA) were unaffected. Our results demonstrate that a single‐hit UPS inhibition is sufficient to induce a stable and selective hyperexcitability phenotype in surviving DA SN neurons in vivo. This might imply that UPS dysfunction sensitizes DA SN neurons by enhancing ‘stressful pacemaking’.     

The Impact of Inpatient Multimodal Treatment or Family-Based Treatment on Six-Month Weight Outcomes in Youth with Anorexia Nervosa: A Naturalistic,Cross-Continental Comparison

In the USA, family-based treatment (FBT) with inpatient medical stabilization as needed is the leading evidence-based treatment for youth with anorexia nervosa (AN). In continental Europe, typically inpatient multimodal treatment targeting weight recovery followed by outpatient care (IMT) is standard care, if prior outpatient treatment was not sufficient. Our aim was to compare weekly weight gain and hospital days over six months for adolescents receiving FBT (USA) versus IMT (Germany) using naturalistic treatment data. To yield similar subgroups of youth aged 12–18 years, inclusion criteria were a percent median BMI (%mBMI) between 70–85 and the restrictive AN subtype. Weight gain and hospital days were compared, adjusted further in a multiple linear regression analysis (MLRA) for baseline group differences. Samples differed on baseline %mBMI (FBT [n = 71], 90.5 ± 12.8; IMT [n = 29], 78.3 ± 9.1, p < 0.05). In subgroups with comparable baseline %mBMI, the weekly weight gain over 6 months was similar (FBT [n = 21]: 0.35 ± 0.18 kg/week; IMT [n = 20]: 0.30 ± 0.18, p = 0.390, p = 0.166 after MLRA), but achieved fewer hospital days in FBT (FBT [n = 7]: 4 ± 6 days, IMT [n = 20]: 121 ± 42 days, p < 0.0001 before and after MLRA). FBT may be effective for a subgroup of adolescents with AN currently receiving IMT, but head-to-head studies in the same healthcare system are needed.