Institute of Orthopedic Research and Biomechanics, University Medical Center Ulm, Ulm, Germany.
Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, University Ulm, Ulm, Germany.
Front Endocrinol (Lausanne). 2022 Sep 15;13:997745. doi: 10.3389/fendo.2022.997745. eCollection 2022.
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/CD11b-Cre, referred to as TH) 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 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 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 mice. This indicates a crucial role of myeloid cell-derived catecholamines in immune cell-bone cell crosstalk and during fracture healing.
儿茶酚胺信号已知会影响骨骼组织，因为随着年龄的增长，从交感神经释放到骨细胞中的去甲肾上腺素的再摄取减少，导致骨质疏松症。此外，β-肾上腺素受体阻滞剂，如普萘洛尔，在骨质疏松症患者中引起骨保护作用。然而，除了全身肾上腺和交感儿茶酚胺的产生，还已知髓样细胞可以合成儿茶酚胺，特别是在炎症条件下。为了研究 CD11b 髓样细胞产生的儿茶酚胺对骨转换和再生的影响，生成了一种在 CD11b 髓样细胞中特异性敲除酪氨酸羟化酶（儿茶酚胺合成的限速酶）的小鼠品系（TH/CD11b-Cre，称为 TH）。为了进行骨骼表型分析，雄性小鼠在 8 周和 12 周龄时被处死，收获的骨骼进行骨长度测量、微计算机断层扫描、骨髓荧光激活细胞分选、基因表达分析、组织学和免疫组织化学分析。12 周龄而非 8 周龄的 TH 小鼠出现骨质疏松表型，骨髓中中性粒细胞和 T 淋巴细胞数量增加，而分选的骨髓髓样细胞中 CCL2、IL-6、IL-4 和 IL-10mRNA 表达降低，这为髓样细胞衍生的儿茶酚胺对骨稳态的年龄依赖性影响提供了支持。为了研究髓样细胞衍生的儿茶酚胺对骨折愈合的影响，小鼠接受了骨干股骨切开术。骨折后 3 天，免疫组织化学显示 TH 小鼠骨折血肿中巨噬细胞、中性粒细胞和细胞毒性 T 淋巴细胞数量增加。第 21 天的微计算机断层扫描显示组织矿物质密度降低、骨体积减少和骨折痂中的小梁减少，表明骨折愈合延迟，可能是由于 TH 小鼠中炎症细胞的增加。这表明髓样细胞衍生的儿茶酚胺在免疫细胞-骨细胞相互作用和骨折愈合过程中起着关键作用。
