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BackgroundImmune reconstitution bone loss (IRBL) is a common side-effect of antiretroviral therapy (ART) in people with human immunodeficiency virus (PWH). Immune reconstitution bone loss acts through CD4+ T-cell/immune reconstitution-induced inflammation and is independent of antiviral regimen. Immune reconstitution bone loss may contribute to the high rate of bone fracture in PWH, a cause of significant morbidity and mortality. Although IRBL is transient, it remains unclear whether bone recovers, or whether it is permanently denuded and further compounds bone loss associated with natural aging.MethodsWe used a validated IRBL mouse model involving T-cell reconstitution of immunocompromised mice. Mice underwent cross-sectional bone phenotyping of femur and/or vertebrae between 6 and 20 months of age by microcomputed tomography (µCT) and quantitative bone histomorphometry. CD4+ T cells were purified at 20 months to quantify osteoclastogenic/inflammatory cytokine expression.ResultsAlthough cortical IRBL in young animals recovered with time, trabecular bone loss was permanent and exacerbated skeletal decline associated with natural aging. At 20 months of age, reconstituted CD4+ T cells express enhanced osteoclastogenic cytokines including RANKL, interleukin (IL)-1β, IL-17A, and tumor necrosis factor-α, consistent with elevated osteoclast numbers.ConclusionsImmune reconstitution bone loss in the trabecular compartment is permanent and further exacerbates bone loss due to natural aging. If validated in humans, interventions to limit IRBL may be important to prevent fractures in aging PWH.

Gender-affirming hormone therapy (GAHT) is often prescribed to transgender (TG) adolescents to alleviate gender dysphoria, but the effect of GAHT on the growing skeleton is unclear. We found GAHT to improve trabecular bone structure via increased bone formation in young male mice and not to affect trabecular structure in female mice. GAHT modified gut microbiome composition in both male and female mice. However, fecal microbiota transfers (FMTs) revealed that GAHT-shaped gut microbiome was a communicable regulator of bone structure and turnover in male, but not in female mice. Mediation analysis identified 2 species of Bacteroides as significant contributors to the skeletal effects of GAHT in male mice, with Bacteroides supplementation phenocopying the effects of GAHT on bone. Bacteroides have the capacity to expand Treg populations in the gut. Accordingly, GAHT expanded intestinal Tregs and stimulated their migration to the bone marrow (BM) in male but not in female mice. Attesting to the functional relevance of Tregs, pharmacological blockade of Treg expansion prevented GAHT-induced bone anabolism. In summary, in male mice GAHT stimulated bone formation and improved trabecular structure by promoting Treg expansion via a microbiome- mediated effect, while in female mice, GAHT neither improved nor impaired trabecular structure., Introduction About 80% of people who are transgender (TG) and people who are gender nonbinary in the US are on long-term gender-affirming hormone therapy (GAHT) to alleviate gender dysphoria and/ [...]

While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here, we report that the deletion of Ptpmt1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection – the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. Ptpmt1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, Ptpmt1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that Ptpmt1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources.

IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including γδ T cells and Th17 cells. However, the origin of these T cells and their relevance for fracture repair are unknown. Here, we show that fractures rapidly expanded callus γδ T cells, which led to increased gut permeability by promoting systemic inflammation. When the microbiota contained the Th17 cell–inducing taxon segmented filamentous bacteria (SFB), activation of γδ T cells was followed by expansion of intestinal Th17 cells, their migration to the callus, and improved fracture repair. Mechanistically, fractures increased the S1P receptor 1–mediated (S1PR1-mediated) egress of Th17 cells from the intestine and enhanced their homing to the callus through a CCL20-mediated mechanism. Fracture repair was impaired by deletion of γδ T cells, depletion of the microbiome by antibiotics (Abx), blockade of Th17 cell egress from the gut, or Ab neutralization of Th17 cell influx into the callus. These findings demonstrate the relevance of the microbiome and T cell trafficking for fracture repair. Modifications of microbiome composition via Th17 cell–inducing bacteriotherapy and avoidance of broad-spectrum Abx may represent novel therapeutic strategies to optimize fracture healing.

Abstract Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the naïve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells/μL (IQR 442-794) in patients aged 50 years or above and 738 cells/μL (IQR 548-1002) in patients aged 18-35 years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count> 500 cells/μL) between the two age groups were 15, 21 and 26% at year 1, 4 years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery.

Activated lymphocytes promote inflammation and bone destruction in rheumatoid arthritis (RA), making T cells and B cells therapeutic targets. Indeed, pharmacological blockade of CD28 costimulation using CTLA-4Ig (abatacept), approved for amelioration of RA, renders T cells dormant (anergic). CTLA-4Ig also promotes bone accretion in healthy mice; surprisingly, however, this effect is driven exclusively through upregulation of bone formation, rather than anti-inflammatory effects on resorption. In the study presented here, we utilized T cell receptor β gene and Wnt-10b gene knockout mice to investigate the roles of T cells and Wnt-10b in CTLA-4Ig-induced bone anabolism. Ablation of either T cells or Wnt-10b not only abolished CTLA-4Ig-induced bone anabolism but also, paradoxically, suppressed bone formation leading to bone loss. Stalled bone formation was accompanied by bone marrow stromal cell expression of the Wnt pathway inhibitor sclerostin. Our data suggest that an immunoskeletal pivot may promote or suppress bone formation, depending on the net outcome of CTLA-4Ig action directed independently on T cells and osteoblast-linage cells that counter Wnt-10b-induced bone anabolism, by secretion of sclerostin. While CTLA-4Ig action is tipped in favor of bone formation under physiological conditions, pathological immunodeficiency may lead to suppressed bone formation and skeletal damage.

IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including [gamma][delta] T cells and Th17 cells. However, the origin of these T cells and their relevance for fracture repair are unknown. Here, we show that fractures rapidly expanded callus [gamma][delta] T cells, which led to increased gut permeability by promoting systemic inflammation. When the microbiota contained the Th17 cell-inducing taxon segmented filamentous bacteria (SFB), activation of [gamma][delta] T cells was followed by expansion of intestinal Th17 cells, their migration to the callus, and improved fracture repair. Mechanistically, fractures increased the S1P receptor 1-mediated (S1PR1-mediated) egress of Th17 cells from the intestine and enhanced their homing to the callus through a CCL20-mediated mechanism. Fracture repair was impaired by deletion of [gamma][delta] T cells, depletion of the microbiome by antibiotics (Abx), blockade of Th17 cell egress from the gut, or Ab neutralization of Th17 cell influx into the callus. These findings demonstrate the relevance of the microbiome and T cell trafficking for fracture repair. Modifications of microbiome composition via Th17 cell-inducing bacteriotherapy and avoidance of broad-spectrum Abx may represent novel therapeutic strategies to optimize fracture healing., Introduction Fracture healing is a complex process involving several sequential phases (1). At first, blood vessels near the injury rupture to form a hematoma, which is rapidly infiltrated by immune [...]

ABSTRACT Cyclic adenosine monophosphate (cAMP)‐dependent phosphodiesterase (PDE) inhibitors such as pentoxifylline (PTX) suppress cAMP degradation and promote cAMP‐dependent signal transduction. PDE inhibitors increase bone formation and bone mass in preclinical models and are used clinically to treat psoriatic arthritis by targeting inflammatory mediators including activated T cells. T cell activation requires two signals: antigen‐dependent CD3‐activation, which stimulates cAMP production; and CD28 co‐stimulation, which downregulates cAMP‐signaling, through PDE activation. PDE‐inhibitors consequently suppress T cell activation by disrupting CD28 co‐stimulation. Interestingly, we have reported that when CD8+ T cells are activated in the absence of CD28 co‐stimulation, they secrete Wnt‐10b, a bone anabolic Wnt ligand that promotes bone formation. In the present study, we investigated whether the bone anabolic activity of the PDE‐inhibitor PTX, has an immunocentric basis, involving Wnt‐10b production by CD8+ T cells. When wild‐type (WT) mice were administered PTX, biochemical markers of both bone resorption and formation were significantly increased, with net bone gain in the axial skeleton, as quantified by micro‐computed tomography (μCT). By contrast, PTX increased only bone resorption in T cell knockout (KO) mice, causing net bone loss. Reconstituting T cell–deficient mice with WT, but not Wnt‐10b knockout (KO) CD8+ T cells, rescued bone formation and prevented bone loss. To study the role of cAMP signaling in Wnt‐10b expression, reverse‐transcription polymerase chain reaction (RT‐PCR) and luciferase‐reporter assays were performed using primary T cells. PDE inhibitors intensified Wnt‐10b promoter activity and messenger RNA (mRNA) accumulation in CD3 and CD28 activated CD8+ T cells. In contrast, inhibiting the cAMP pathway mediators protein kinase A (PKA) and cAMP response element‐binding protein (CREB), suppressed Wnt‐10b expression by T cells activated in the absence of CD28 co‐stimulation. In conclusion, the data demonstrate a key role for Wnt‐10b production by CD8+ T cells in the bone anabolic response to PDE‐inhibitors and reveal competing T cell–independent pro‐resorptive properties of PTX, which dominate under T cell–deficient conditions. Selective targeting of CD8+ T cells by PDE inhibitors may be a beneficial approach for promoting bone regeneration in osteoporotic conditions. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells into mice, we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal NK cells and Th1 cells and their migration from the gut to tumor-bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated intestinal egress of NK and Th1 cells, or inhibition of their CXCR3/CXCL9-mediated influx into the BM, prevented the expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in patients with melanoma.

T cells are involved in the bone loss induced by parathyroid hormone (PTH), but their origin is unknown. Here, the authors show that the intestinal microbiota is required for PTH to induce bone loss and describes mechanisms for microbiota-mediated gut–bone crosstalk in mouse models of hyperparathyroidism.

Purpose We describe the rationale for and design of an innovative, nested, tripartite prospective observational cohort study examining whether relative estrogen insufficiency-induced inflammation amplifies HIV-induced inflammation to cause end organ damage and worsen age-related co-morbidities affecting the neuro-hypothalamic-pituitary-adrenal axis (Brain), skeletal (Bone), and cardiovascular (Heart/vessels) organ systems (BBH Study). Methods The BBH parent study is the Multicenter AIDS Cohort/Women’s Interagency HIV Study Combined Cohort Study (MWCCS) with participants drawn from the Atlanta MWCCS site. BBH will enroll a single cohort of n = 120 women living with HIV and n = 60 HIV-negative women, equally distributed by menopausal status. The innovative multipart nested study design of BBH, which draws on data collected by the parent study, efficiently leverages resources for maximum research impact and requires extensive oversight and management in addition to careful implementation. The presence of strong infrastructure minimized BBH study disruptions due to changes in the parent study and the COVID-19 pandemic. Conclusion BBH is poised to provide insight into sex and HIV associations with the neuro-hypothalamic-pituitary-adrenal axis, skeletal, and cardiovascular systems despite several major, unexpected challenges.

Parathyroid hormone (PTH) is a critical regulator of skeletal development that promotes both bone formation and bone resorption. Using microbiota depletion by wide-spectrum antibiotics and germ-free (GF) female mice, we showed that the microbiota was required for PTH to stimulate bone formation and increase bone mass. Microbiota depletion lowered butyrate levels, a metabolite responsible for gut-bone communication, while reestablishment of physiologic levels of butyrate restored PTH-induced anabolism. The permissive activity of butyrate was mediated by GPR43 signaling in dendritic cells and by GPR43-independent signaling in T cells. Butyrate was required for PTH to increase the number of bone marrow (BM) regulatory T cells (Tregs). Tregs stimulated production of the osteogenic Wnt ligand Wnt10b by BM [CD8.sup.+] T cells, which activated Wnt-dependent bone formation. Together, these data highlight the role that butyrate produced by gut luminal microbiota plays in triggering regulatory pathways, which are critical for the anabolic action of PTH in bone., Introduction Parathyroid hormone (PTH) is a calciotrophic hormone produced by the parathyroid glands. PTH is a critical regulator of skeletal development and postnatal skeletal maturation due to its capacity to [...]

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells into mice, we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal NK cells and Th1 cells and their migration from the gut to tumor-bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated intestinal egress of NK and Th1 cells, or inhibition of their CXCR3/CXCL9-mediated influx into the BM, prevented the expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in patients with melanoma., Introduction Microorganisms that inhabit the gut lumen are increasingly recognized as being critical to health and disease (1). One tissue now known to be regulated by the gut microbiome is [...]

Occupants can provide valuable feedback on the indoor environmental quality of buildings. Research on occupant voting systems (OVS) has demonstrated that apps or electronic devices can act as viable tools for collecting long-term feedback from occupants. However, previous research has only to a limited extent explored occupants’ interaction with OVS and the impact it might have on the reliability of the collected feedback. The present paper presents three case studies on applying a tangible OVS, denoted TiAQ, to collect feedback on thermal and indoor air quality (IAQ) in office spaces. The main objective of the present study was first to explore occupants’ interaction with TiAQ and their motivation. Second, identifying whether feedback collected with TiAQ could represent occupants’ comfort and discomfort with the thermal environment and IAQ. Thirdly, identifying challenges related to occupants’ interaction with TiAQ that might affect the representativeness of collected feedback. The present study was conducted at three office buildings in up to 7 months and demonstrated that TiAQ was suitable for collecting long-term feedback on occupants’ comfort and discomfort with the thermal environment. On average, one vote was cast per day per occupant. Additionally, in one of the office buildings, 60% of occupants reported to have interacted with TiAQ daily or weekly when, e.g., passing the device going to/from the office spaces. Occupants’ expectations of TiAQ and getting “feedback on feedback” need to be further addressed to identify ways to sustain occupants’ long-term use of the device and reduce “ill-willed” interactions.