Steven L. Teitelbaum

Talc pleurodesis is highly effective for preventing recurrence of pneumothorax and pleural effusion, but it can be complicated by dissemination, acute lung injury, lead exposure, and foreign body–induced chronic inflammation and pain. Our objective is to develop a safe, biodegradable, contaminant-free particle for pleurodesis. We used mouse models of pneumothorax and malignant pleural effusion to compare the efficacy and safety of pleurodesis with talc and hydroxyapatite microspheres (HAM). Intrapleural instillation of microspheres induced pleural adhesions, fibrosis, and symphysis as effectively as talc and resulted in more durable protection from experimental pneumothorax. HAM and talc both induced an osteoclastogenic, inflammatory, and fibrotic response in pleural lavage cells. Intrapleural HAM was resorbed by osteoclast action over 3 months, whereas talc was not cleared. Deletion of the osteoclast effector, CTSK, diminished pleural adhesion formation and fibrosis by HAM, and inhibition of osteoclastogenesis with anti-RANKL antibody delayed HAM clearance. We found no difference in activity level, feeding behavior, or lung compliance between particles, but talc induced more persistent pleural inflammation. We conclude that HAM resulted in an osteoclastogenic and fibrogenic pleural response that induced pleurodesis that was more durable than talc with a superior safety profile due in part to osteoclast-mediated particle clearance.

Treatment of osteoporosis commonly diminishes osteoclast number which suppresses bone formation thus compromising fracture prevention. Bone formation is not suppressed, however, when bone degradation is reduced by retarding osteoclast functional resorptive capacity, rather than differentiation. We find deletion of deubiquitinase, BRCA1-associated protein 1 (Bap1), in myeloid cells (Bap1^∆LysM), arrests osteoclast function but not formation. Bap1^∆LysM osteoclasts fail to organize their cytoskeleton which is essential for bone degradation consequently increasing bone mass in both male and female mice. The deubiquitinase activity of BAP1 modifies osteoclast function by metabolic reprogramming. Bap1 deficient osteoclast upregulate the cystine transporter, Slc7a11, by enhanced H2Aub occupancy of its promoter. SLC7A11 controls cellular reactive oxygen species levels and redirects the mitochondrial metabolites away from the tricarboxylic acid cycle, both being necessary for osteoclast function. Thus, in osteoclasts BAP1 appears to regulate the epigenetic-metabolic axis and is a potential target to reduce bone degradation while maintaining osteogenesis in osteoporotic patients.

Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.

Both LRF (Zbtb7a) and ThPOK (Zbtb7b) belong to the POK (BTB/POZ and Kruppel) family of transcription repressors that participate in development, differentiation, and oncogenesis. Although LRF mediates osteoclast differentiation by regulating NFATc1 expression, the principal established function of ThPOK is transcriptional control of T‐cell lineage commitment. Whether ThPOK affects osteoclast formation or function is not known. We find that marrow macrophage ThPOK expression diminishes with exposure to receptor activator of NF‐kB ligand (RANKL), but ThPOK deficiency does not affect osteoclast differentiation. On the other hand, enhanced ThPOK, in macrophages, substantially impairs osteoclastogenesis. Excess ThPOK binds the NFATc1 promoter and suppresses its transcription, suggesting a mechanism for its osteoclast inhibitory effect. Despite suppression of osteoclastogenesis by excess ThPOK being associated with diminished NFATc1, osteoclast formation is not rescued by NFATc1 overexpression. Thus, ThPOK appears to inhibit NFATc1 transcription and its osteoclastogenic capacity, while its depletion has no effect on the bone‐resorptive cell. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Cardiac arrest is a rare but reported complication during breast augmentation surgery. It is even more rare in a reportedly healthy patient without preexisting cardiac disease. The authors present the case of a healthy 34-year-old female who underwent elective bilateral augmentation mammaplasty and experienced unanticipated asystolic cardiac arrest intraoperatively following general anesthesia supplemented by a regional pectoral (pec I) nerve block. The performing plastic surgeon provided cardiopulmonary resuscitation while the anesthesiologist initiated a rescue protocol per Advanced Cardiac Life Support (ACLS) guidelines. Fortunately, the patient was resuscitated in a timely manner and had a successful return of spontaneous circulation within 1 minute. This case report serves to briefly review the literature and recommendations on proper resuscitation of cardiac arrest per ACLS protocols as well as discuss unstable bradycardia in otherwise healthy patients undergoing breast augmentation surgery. Plastic surgeons and anesthesiologists who perform this procedure should be aware of the possible, rare but serious progression to asystole as well as the proper resuscitative measures to take should they be required. Level of Evidence: 5:

Cell Metab 2021;33(2): 270–282.e8. doi: https://doi.org/10.1016/j.cmet.2020.11.008 Brestoff et al. show, for the first time, that mitochondria are transferred from adipocytes to macrophages and that this event has an impact on systemic metabolic homeostasis.Within the last years, it has been demonstrated that cells are able to communicate with each other by the exchange of organelles, such as lysosomes and mitochondria, and this gained considerable interest in different fields of medicine. Intercellular exchange of mitochondria can take place by several mechanisms, including tunnelling microtubes, extracellular vesicles, or cell fusion (1). Moreover, mitochondria appear to be transported systemically as well, as they are frequently found in the circulation (2). Whether or not mitochondrial transfer takes place in the adipose tissue had not been investigated so far. The authors used a transplantation mouse model, in which mitochondria in the adipose tissue were specifically labelled. They showed a directed transfer of mitochondria from adipocytes to macrophages, which was dependent on the presence of heparan sulphate on the surface of macrophages. This transport was diminished in high-fat-diet (HDF) obesity, and conversely, inhibition of mitochondrial transfer resulted in metabolic dysfunction. Overall, these findings clearly demonstrates that adipocyte-macrophage exchange is relevant for obesity development. Still, it would have been desirable to unravel the mechanism of mitochondrial exchange in more detail. As the fluorescent images implicate, it seems that mitochondria are taken up into macrophages by endocytosis, which is the major function of these cells. It would have been interesting to know the mechanisms that prevent macrophages from degrading mitochondria, and instead utilise them. Further research might address whether intercellular organelle transport takes place in humans as well. The presence of mitochondria in the bloodstream (2) suggests that this might be true, and opens up new avenues for the study of intercellular or inter-organ communication in humans. References: 1. Murray, L. M. A. & Krasnodembskaya, A. D. Concise Review: Intercellular Communication Via Organelle Transfer in the Biology and Therapeutic Applications of Stem Cells. Stem Cells 37, 14–25 (2019).2. Al Amir Dache, Z. et al. Blood contains circulating cell-free respiratory competent mitochondria. FASEB J. 34, 3616–3630 (2020).