Erythropoietin (EPO) is a key regulator of erythropoiesis, and it is mainly used to treat anemia. However, it is also administered prophylactically to non-anemic patients in certain clinical settings and is known to be used illicitly by athletes. The effect of EPO is controversial but emerging evidence indicates that EPO treatment induces bone loss in healthy mice. Here, we investigated the immediate and short-term skeletal effects of a single high-dose EPO injection in young mature (9 weeks) female mice. Cellular and molecular markers of bone turnover were evaluated at multiple time points post-injection. EPO administration led to a rapid increase in macrophage colony-stimulating factor (M-CSF) levels within the bone marrow (BM) microenvironment and in the serum, accompanied by an increase in BM CD115-positive cells and osteoclast precursors, as assessed by flow cytometry. This early cellular response to EPO was followed by an increase in tartrate-resistant acid phosphatase 5b (TRAP5b) and a decrease in procollagen type 1 N-terminal propeptide (P1NP), as determined by serum ELISA analyses, suggesting increased osteoclast numbers and decreased bone formation, respectively. Micro-computed tomography (μCT) revealed a significant reduction in trabecular bone volume. These findings demonstrate that even a single high-dose EPO injection disrupts bone homeostasis and induces significant bone loss through early modulation of the BM niche and osteoclastogenic pathways. Our results have important clinical implications for the prophylactic use of EPO and highlight potential skeletal risks.

Cardiovascular disease and osteoporosis are clinically associated. Bone adapts to mechanical forces by altering its overall structure and mass. In response to mechanical strain bone cells release signaling molecules and activate the nervous system. Bone also exhibits endocrine functions that modulate a number of tissues including the heart. We hypothesized that bone mechanical loading acutely alters cardiac function via neural and/or endocrine mechanisms. To test this hypothesis, we performed in vivo tibia mechanical loading in anesthetized mice while monitoring heart parameters using electrocardiogram (ECG). An immediate, transient reduction in resting heart rate was observed during tibial loading in both adult male and female mice (p<0.01) with concurrent increases in heart rate variability (HRV) (p<0.01). ECG intervals, PR, QRS and QTc were unaffected with loading. In further studies, we found that at least 3N of load was necessary to elicit this heart response in adult mice. With aging to 11-12months the responsiveness of the heart to loading was blunted, suggesting this bone-heart connection may weaken with age. Administration of lidocaine around the tibia significantly diminished the heart rate response to bone loading (p<0.05). Moreover, pre-treatment with sympathetic antagonist propranolol inhibited this heart rate response to loading (p<0.05), while parasympathetic antagonist atropine did not (p>0.05). This suggests that a neuronal afferent pathway in the hindlimb and reduction in efferent sympathetic tone mediate this bone-neuro-heart reflex. In conclusion, the findings that tibia bone loading age-dependently modulates heart function support the concept of physiological coupling of the skeletal and cardiovascular systems.

Titanium (Ti) is widely acknowledged as the top choice for constructing dental implants because of its remarkable biocompatibility and biomechanical characteristics. Its rapid oxidation in the presence of oxygen forms a protective titanium dioxide (TiO2) layer on the implants' surface, ensuring resistance to corrosion. This thin oxide layer plays a crucial role in establishing the favorable biocompatibility of Ti implants. However, under mechanical loading conditions, the integrity of the TiO2 layer can be compromised through the dynamic interactions between the implant and bone tissue, leading to localized damage and subsequent corrosion. This corrosion weakens the implant and may result in the release of metallic particles or ions into the surrounding living tissues. Consequently, corrosion serves as a potential catalyst for the emergence of malfunctions in dental implants, whether biological or mechanical in nature. To address this issue, extensive research has focused on nanoscale surface modifications aimed at enhancing the durability and resistance to chemical and electrochemical changes exhibited by dental implants made from Ti. Hence, this narrative review specifically examines nano surface modifications of titanium dental implants, focusing on their effects on corrosion resistance, biomechanical performance, and osseointegration, distinguishing it from other reviews that address broader aspects of titanium implants or general corrosion mechanisms.

Excessive production of Transforming Growth Factor β (TGFβ) is commonly associated with dominant and recessive forms of OI. Previous reports have indicated that administration of TGFβ-targeted antibodies maybe of potential therapeutic benefit to OI patients. However, direct targeting of TGFβ is likely to cause multiple adverse effects including simulation of autoimmunity. In the current study we use patient-derived normal and OI fibroblasts, osteoblasts and OIM mouse models to determine the effects of Losartan, an angiotensin II receptor type 1 (AT1) antagonist, on TGFβ signalling and bone morphology in OI. In OIM mice bred on a mixed background administration of 0.6 g/L losartan for 4 weeks was associated with a significant reduction in TGFβ from 79.2 g/L in the control to 60.0 ng/ml following losartan (p < 0.05), reduced osteoclast activity as measured by CTX from 275.9 ng/ml in the control to 157.2 ng/ml following 0.6 g/L of losartan (p < 0.05) and increased cortical bone thickness (P < 0.001). Furthermore in OIM mice bred on a C57BL/6 background 0.6 g/L losartan increased trabecular bone volume in the tibiae (P < 0.05) and the vertebrae (P < 0.01), increased cortical bone thickness (P < 0.001) reduced the trabecular pattern factor (P < 0.01 and P < 0.001 for the tibiae and vertebrae respectively), reduced osteoclast (P < 0.05) and osteoblast (P < 0.01) numbers as well as reducing the area of bone covered by these cell types. Interestingly, losartan did not affect immune cells infiltrating into bone, nor did this drug alter TGFβ signalling in normal or OI fibroblasts. Instead, losartan reduced SMAD2 phosphorylation in osteoblasts, inhibiting their ability to differentiate. Our data suggest that losartan may be an effective treatment for the bone-associated dysmorphia displayed in OI whilst minimising potential adverse immune cell-related effects.

Multicentric osteolysis nodulosis and arthropathy (MONA) is a rare skeletal dysplasia characterized primarily by progressive osteolysis, particularly affecting the carpal and tarsal bones, accompanied by osteoporosis. In addition, it features subcutaneous nodules on the palms and soles, along with the progressive onset of arthropathy, encompassing joint contractures, pain, swelling and stiffness. It is caused by a deficiency of the Matrix Metalloproteinase-2 (MMP2). In the current study we present a comprehensive clinical, radiological, genetic and in silico analysis of MONA in a consanguineous Pakistani family. Clinical and radiological examinations of the three severely affected siblings demonstrated a progressive MONA syndrome with phenotypic variability. The patients presented unusual facial appearance, thickened skin, severe short stature, short hands and feet. Radiographs revealed extensive bone deformities affecting upper and lower arms, legs, vertebrae and hip. Genetic analysis revealed a homozygous missense variant [c.539 A > T p.(Asp180Val)] in the MMP2 gene. In silico findings suggested a mutant MMP2 protein with a decreased stability and an altered pattern of interactions. Our findings add to the existing literature on the skeletal phenotype of MONA syndrome, including the specific clinical and radiological patterns observed. Moreover, the study will aid in genetic counseling and accurate diagnosis of families affected by the same disorder within the Pakistani population.

PurposeDairy foods are nutritional sources of calcium, phosphorus, protein, and other nutrients that improve bone health. However, the effects of dairy consumption on bone biomarkers in the Japanese population remain unclear. This study explored the association between dairy consumption and bone biomarkers in Japanese adults. MethodsThis cross-sectional study was conducted as part of the Iwaki Health Promotion Project in Aomori, Japan. In total, 1063 adults were included in the analysis. Bone turnover marker levels were measured in local citizens during their annual medical checkups. The calcaneus osteo sono assessment index (OSI) was calculated using a quantitative ultrasound technique. The dietary intake of foods and nutrients was estimated using a food frequency questionnaire. Linear regression models were established using dairy consumption and bone biomarkers with adjustments. Statistic significance was considered by P < 0.05. ResultsIn multivariate models, the tartrate-resistant acid phosphatase 5b and parathyroid hormone concentrations were inversely associated with dietary dairy consumption after adjusting for age and sex. The undercarboxylated osteocalcin, a procollagen type I N-terminal peptide to bone alkaline phosphatase ratio, and OSI were the directly associated with dairy consumption in multivariate models with adjustment. ConclusionsDairy consumption is partially associated with bone turnover biomarkers and OSI in adult Japanese participants. Habitual consumption of dairy foods may contribute to the nutritional supplementation for maintaining bone health, including turnover and structure. Clinical trial registry number and website where it was obtainedThe Japanese Clinical Trials Registry (UMIN000040459), https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000046175.