A potential association between hematopoietic stem cell status in the bone marrow and the surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes deriving from bone marrow mononuclear cells and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.

The nature of bone homeostasis is the coordination between the osteoblasts (OBs) and osteoclasts (OCs). However, abnormal activation of osteoclasts (OCs) could compromise the bone homeostasis. Thus, it is imperatively urgent to explore effective medical interventions for patients. NO/guanylate cyclase (GC)/cGMP signaling cascade has been widely reported in regulating bone metabolism, and GC plays a significantly critical role. Vericiguat, a novel oral soluble guanylate cyclase (sGC) stimulator, has been firstly reported in 2020 to treat patients with heart failure. However, the effect of Vericiguat on the function of OCs has not been explored. In this present study, we found that the concentration range of Vericiguat between 0-8uM was none- cytotoxic to BMMs. Vericiguat could enhance differentiation of OCs at concentration of 500nM, whereas it inhibited differentiation at 8 uM in terms of the number and size of OCs. In addition, Veirciguat also showed dural effect on RANKL‐induced OC fusion and bone resorption in a concentration‐dependent manner. Further, molecular assay suggested that the dually regulatory effect of Vericiguat on OCs was mediated by the bidirectional activation of IκB-α/NF-κB signaling pathway. Taken together, our present study demonstrated the dual effects of Vericiguat on the formation of functional OCs in a concentration-dependent manner. The regulatory effect of Vericiguat on OCs was mediated by the bidirectional activation of IκB-α/ NF-κB signaling pathway, and a potential balance between IκB-α/ NF-κB signaling pathway and sGC/cGMP/VASP may exist.

Bone involvement occurs in 75% of patients with Gaucher disease (GD), and comprises structural changes, debilitating pain, and bone density abnormalities. Osteoporosis is a silent manifestation of GD until a pathologic fracture occurs. Thus early diagnosis is crucial for identifying high-risk patients to prevent irreversible complications. Thirty-one patients with GD were assessed prospectively to identify predictive markers associated with bone density abnormalities, osteopenia (OSN), and osteoporosis (OSR). Subjects were categorized into three cohorts based on T- or Z- scores of bone mineral density (BMD): In GD cohort with no bone complication (Z-score≥-0.9; T-scores≥-1), the OSN group (-1.8 ≥ Z-score ≥ -1; -2.5 ≥ T-score ≥ -1) and OSR group (Z-score ≤ -1.9; T-scores ≤ -2.5). Serum levels of TRAP5b, RANKL, OPG, and RANK were quantified by enzyme-linked immunosorbent assays. TRAP5b was increased in GD and showed a positive correlation with GD biomarkers, including plasma glucosylsphingosine (Lyso-Gb1), macrophage activation markers CCL18 and chitotriosidase. The highest levels of TRAP5b was measured in patients with osteoporosis. The elevation of RANKL and RANKL/OPG ratio correlated with osteopenia in GD. Elevation of TRAP5b, RANKL, and RANKL/OPG indicate osteoclast activation in GD. TRAP5b is a potential bone biomarker for GD with the ability to predict the progression of bone density abnormalities.

Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question whether OPG expression responds to treatment. Therefore, we aimed to elucidate the regulation of OPG production and its biological activity in human and mouse livers. OPG levels were significantly higher in lysates of human cirrhotic and mouse fibrotic livers compared to healthy livers. Hepatic OPG expression localized in cirrhotic collagenous bands in and around myofibroblasts. Single cell sequencing of murine liver cells showed hepatic stellate cells (HSC) to be the main producers of OPG in healthy livers. Using mouse precision-cut liver slices, we found OPG production induced by transforming growth factor β1 (TGFβ1) stimulation. Moreover, OPG itself stimulated expression of genes associated with fibrogenesis in liver slices through TGFβ1, suggesting profibrotic activity of OPG. Resolution of fibrosis in mice was associated with significantly lower OPG levels in livers as compared to their fibrotic counterparts.OPG stimulates fibrogenesis through TGFβ1 and is closely associated with the degree of fibrogenesis. It may therefore be a novel drug target for liver fibrosis or be used as a biomarker for treatment success of novel antifibrotics.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator ok NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.

Astronauts are at risk of losing 1.0 to 1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs and dietary regimens designed to preserve their musculoskeletal system. This loss is the result of microgravity-related impairment of osteocyte and osteoblast function and the consequent upregulation of osteoclast-mediated bone resorption. This review describes the ontogeny of osteoclast hematopoietic stem cells, the contributions of macrophage colony stimulating factor, activator of NFkB and the calcineurin pathways make in osteoclast differentiation, and provides details of bone formation, the osteoclast cytoskeleton, the immune regulation of osteoclasts, and osteoclast mechanotransduction on Earth, in the microgravity of space, and in conditions of simulated microgravity. The article discusses the need to better understand how osteoclasts are able to function in zero gravity and reviews current and prospective therapies that may be used to treat osteoclast-mediated bone disease.

Butyric acid as a histone deacetylase (HDAC) inhibitor was produced by a number of periodontal and root canal microorganisms (such as Porphyromonas, Fusobacterium etc.). Butyric acid may affect the biological activities of periodontal/periapical cells such as osteoblasts, periodontal ligament cells etc., and thus affect periodontal/periapical tissue destruction and healing. The purposes of this study were to study the toxic effects of butyrate on matrix and mineralization markers’ expression of MG-63 osteoblasts. Cell viability and proliferation were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cellular apoptosis and necrosis were analyzed by propidium iodide/Annexin V flow cytometry. Protein and mRNA expression of OPG, and RANKL were analyzed by western blotting and RT-PCR. OPG, soluble RANKL (sRANKL), 8-isoprostane, pro-collagen I, MMP-2, osteonectin (SPARC), osteocalcin and osteopontin secretion into culture medium were measured by enzyme-linked immunosorbant assay. Histone H3 acetylation levels were evaluated by immunofluorescent staining (IF) and western blot. We found that butyrate induced morphologic changes of growing MG-63 cells, with bigger and flattened in appearance. Butyrate activated histone H3 acetylation of MG-63 cells. Exposure of MG-63 cells to butyrate partly decreased cell number with no marked increase in apoptosis and necrosis. Butyrate stimulated RANKL protein expression, whereas it inhibited OPG protein expression. Butyrate also inhibited the secretion of OPG in MG-63 cells, whereas sRANKL level was below detection limit. Butyrate stimulated 8-isoprostane, MMP-2 and osteopontin secretion, but not procollagen I, osteonectin, osteocalcin in MG-63 cells. In conclusion, butyric acid generated by periodontal and root canal microorganisms may potentially induce bony destruction and impair bone repair by alteration of OPG/RANKL expression/secretion, 8-isoprostane, MMP-2, and osteopontin secretion, and affect cell proliferation. These effects are possibly related to increased histone acetylation. These events are important in the pathogenesis of periodontal and periapical destruction.