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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., (© 2024. The Author(s).)

External mechanostimulation applied by whole-body low-magnitude high-frequency vibration (LMHFV) was demonstrated to cause no or negative effects on fracture healing in estrogen-competent rodents, while in ovariectomized (OVX), estrogen-deficient rodents bone formation after fracture was improved. Using mice with an osteoblast-specific deletion of the estrogen receptor α (ERα), we demonstrated that ERα signaling in osteoblasts is required for both the anabolic and catabolic effects of LMHFV during bone fracture healing in OVX and non-OVX mice, respectively. Because the vibration effects mediated by ERα were strictly dependent on the estrogen status, we hypothesized different roles of ligand-dependent and -independent ERα signaling. To investigate this assumption in the present study, we used mice with a deletion of the C-terminal activation function (AF) domain-2 of the ERα receptor, which mediated ligand-dependent ERα signaling (ERαAF-2 0 ). OVX and non-OVX ERαAF-2 0 animals were subjected to femur osteotomy followed by vibration treatment. We revealed that estrogen-competent mice lacking the AF-2 domain were protected from LMHFV-induced impaired bone regeneration, while the anabolic effects of vibration in OVX mice were not affected by the AF-2 knockout. RNA sequencing further showed that genes involved in Hippo/Yap1-Taz and Wnt signaling were significantly downregulated upon LMHFV in the presence of estrogen in vitro. In conclusion, we demonstrated that the AF-2 domain is crucial for the negative effects of vibration during bone fracture healing in estrogen-competent mice suggesting that the osteoanabolic effects of vibration are rather mediated by ligand-independent ERα signaling., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding that study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Mental traumatization is associated with long-bone growth retardation, osteoporosis and increased fracture risk. We revealed earlier that mental trauma disturbs cartilage-to-bone transition during bone growth and repair in mice. Trauma increased tyrosine hydroxylase-expressing neutrophils in bone marrow and fracture callus. Here we show that tyrosine hydroxylase expression in the fracture hematoma of patients correlates positively with acknowledged stress, depression, and pain scores as well as individual ratings of healing-impairment and pain-perception post-fracture. Moreover, mice lacking tyrosine hydroxylase in myeloid cells are protected from chronic psychosocial stress-induced disturbance of bone growth and healing. Chondrocyte-specific β2-adrenoceptor-deficient mice are also protected from stress-induced bone growth retardation. In summary, our preclinical data identify locally secreted catecholamines in concert with β2-adrenoceptor signalling in chondrocytes as mediators of negative stress effects on bone growth and repair. Given our clinical data, these mechanistic insights seem to be of strong translational relevance., (© 2023. The Author(s).)

Bone has the rare capability of scarless regeneration that enables the complete restoration of the injured bone area. In recent decades, promising new technologies have emerged from basic, translational and clinical research for fracture treatment; however, 5-10 % of all bone fractures still fail to heal successfully or heal in a delayed manner. Several comorbidities and risk factors have been identified which impair bone healing and might lead to delayed bone union or non-union. Therefore, a considerable amount of research has been conducted to elucidate molecular mechanisms of successful and delayed fracture healing to gain further insights into this complex process. One focus of recent research is to investigate the complex interactions of different cell types and the action of progenitor cells during the healing process. Of particular interest is also the identification of patient-specific comorbidities and how these affect fracture healing. In this review, we discuss the recent knowledge about progenitor cells for long bone repair and the influence of comorbidities such as diabetes, postmenopausal osteoporosis, and chronic stress on the healing process. The topic selection for this review was made based on the presented studies at the 2022 annual meeting of the European Calcified Tissue Society (ECTS) in Helsinki., Competing Interests: We do not have a conflict of interest regarding that manuscript. The work was done in the framework of projects funded from the German Research Foundation (HA 8470/1-1 and 251293561 SFB1149)., (© 2023 The Authors. Published by Elsevier Inc.)

Catecholamine signaling is known to influence bone tissue as reuptake of norepinephrine released from sympathetic nerves into bone cells declines with age leading to osteoporosis. Further, β-adrenoceptor-blockers like propranolol provoke osteoprotective effects in osteoporotic patients. However, besides systemic adrenal and sympathetic catecholamine production, it is also known that myeloid cells can synthesize catecholamines, especially under inflammatory conditions. To investigate the effects of catecholamines produced by CD11b + myeloid cells on bone turnover and regeneration, a mouse line with specific knockout of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, in CD11b + myeloid cells (TH flox/flox /CD11b-Cre + , referred to as TH CD11b-Cre ) was generated. For bone phenotyping, male mice were sacrificed at eight and twelve weeks of age and harvested bones were subjected to bone length measurement, micro-computed tomography, fluorescence-activated cell sorting of the bone marrow, gene expression analysis, histology and immunohistochemistry. Support for an age-dependent influence of myeloid cell-derived catecholamines on bone homeostasis is provided by the fact that twelve-week-old, but not eight-week-old TH CD11b-Cre mice, developed an osteopenic phenotype and showed increased numbers of neutrophils and T lymphocytes in the bone marrow, while CCL2, IL-6, IL-4 and IL-10 mRNA expression was reduced in sorted myeloid bone marrow cells. To investigate the influence of myeloid cell-derived catecholamines on fracture healing, mice received a diaphyseal femur osteotomy. Three days post-fracture, immunohistochemistry revealed an increased number of macrophages, neutrophils and cytotoxic T lymphocytes in the fracture hematoma of TH CD11b-Cre mice. Micro-computed tomography on day 21 showed a decreased tissue mineral density, a reduced bone volume and less trabeculae in the fracture callus indicating delayed fracture healing, probably due to the increased presence of inflammatory cells in TH CD11b-Cre mice. This indicates a crucial role of myeloid cell-derived catecholamines in immune cell-bone cell crosstalk and during fracture healing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kuhn, Haffner-Luntzer, Kempter, Reber, Ichinose, Vacher, Ignatius and Tschaffon-Müller.)