Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1^Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1^Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1^Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined.

Bone tissue in vertebrates is essential to performing movements, to protecting internal organs and to regulating calcium homeostasis. Moreover, bone has also been suggested to contribute to whole-body physiology as an endocrine organ, affecting male fertility; brain development and cognition; and glucose metabolism. A main determinant of bone quality is the constant remodeling carried out by osteoblasts and osteoclasts, a process consuming vast amounts of energy. In turn, clinical conditions associated with impaired glucose metabolism, including type I and type II diabetes and anorexia nervosa, are associated with impaired bone turnover. As osteoblasts are required for collagen synthesis and matrix mineralization, they represent one of the most important targets for pharmacological augmentation of bone mass. To fulfill their function, osteoblasts primarily utilize glucose through aerobic glycolysis, a process which is regulated by various molecular switches and generates adenosine triphosphate rapidly. In this regard, researchers have been investigating the complex processes of energy utilization in osteoblasts in recent years, not only to improve bone turnover in metabolic disease, but also to identify novel treatment options for primary bone diseases. This review focuses on the metabolism of glucose in osteoblasts in physiological and pathophysiological conditions.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β ₂ -adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene–related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Background: The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. Methods: Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP^−/−_aged) were compared to, first, age-matched wild type (WT_aged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP^−/−_CTRL) and non-OA WT animals (WT_CTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. Results: WT_aged mice exhibited elevated αCGRP serum levels compared to young WT_CTRL animals. Marked signs of OA-induced cartilage destruction were seen in WT_aged animals, while αCGRP^−/−_aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WT_aged but not in αCGRP^−/−_aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. Conclusions: Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

Numerous studies have reported the relationship between Long non-coding RNAs (LncRNAs) expression and prognosis of osteosarcoma, but less consensus has been reached. Our meta-analysis was conducted to quantitatively assess the relationship between the expression of LncRNAs, prognosis and clinical pathology in osteosarcoma development. PubMed,Embase,Web of Science,The Cochrane Library,SionMed,CNKI and WanFang databases were carefully searched to identify eligible studies. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate the prognostic significance of LncRNAs expression in osteosarcoma. Moreover, meta-regression analysis and subgroup analysis were carried out to explore the potential sources of heterogeneity. A total of 20 studies comprising 1749 patients were included in present meta-analysis. The results showed that the over-expression of LncRNA had a significant correlation with overall survival (OS) (HR = 2.16, 95% CI:1.68-2.79), and was not related to disease free survival (DFS) (HR = 0.71, 95% CI:0.05-9.53). Subgroup analysis further indicated that LncRNA transcription level was significantly associated with alkaline phosphatase (HR = 2.13, 95% CI:1.58-2.88) , tumor size (< 8/ ≥ 8:HR = 1.97, 95% CI: 1.55-2.62) , metastasis (yes/no: HR = 2.14,95% CI:1.15-3.97) , distant metastasis(presence/absence: HR = 4.02, 95% CI:3.05-5.23) and Enneking stage(IIA /IIB-III:HR = 3.2, 95% CI:2.48-4.14), but not associated with age (≤ 25/ > 25:HR = 1.01, 95% CI:0.78-1.3), gender(female/male: HR = 1.15, 95% CI: 0.96-1.37), tumor site (femur,tibia/elsewhere:HR = 1.15, 95% CI:0.94-1.4) and chemotherapy (yes/no: HR = 1.45, 95% CI:0.46-4.63). This study demonstrated that abnormal LncRNAs expression might be potential prognostic markers to predict worse overall survival in osteosarcoma patients. However, the cut-off values may be the source of heterogeneity.