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Estrogen regulation of myokines that enhance osteoclast differentiation and activity.

ABSTRACT: Osteoporosis and sarcopenia are maladies of aging that negatively affect more women than men. In recent years, it has become apparent that bone and muscle are coupled not only mechanically as muscle pulls on bone, but also at a higher level with myokines, biochemical and molecular signaling occurring between cells of the two tissues. However, how estrogen deficiency in females impacts the chemical crosstalk between bone and muscle cells is not understood. We hypothesize that changes in estrogen signaling alters myokine expression and intensifies bone loss in women. In our present study, we demonstrate that conditioned media from ovariectomized or skeletal muscle deficient in estrogen receptor α (ERα) expression enhances osteoclast differentiation and activity. Using a cytokine array, we identified myokines that have altered expressions in response to loss of estrogen signaling in muscle. Lastly, we demonstrate that conditional deletion of ERα in skeletal muscle results in osteopenia due to an increase in the osteoclast surface per bone surface. Our results suggest that estrogen signaling modulates expression of myokines that regulate osteoclast differentiation and activity.

SUBMITTER: Norton A

PROVIDER: S-EPMC9508086 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Estrogen regulation of myokines that enhance osteoclast differentiation and activity.

Norton Andrew A Thieu Kathleen K Baumann Cory W CW Lowe Dawn A DA Mansky Kim C KC

Scientific reports 20220923 1

Osteoporosis and sarcopenia are maladies of aging that negatively affect more women than men. In recent years, it has become apparent that bone and muscle are coupled not only mechanically as muscle pulls on bone, but also at a higher level with myokines, biochemical and molecular signaling occurring between cells of the two tissues. However, how estrogen deficiency in females impacts the chemical crosstalk between bone and muscle cells is not understood. We hypothesize that changes in estrogen ...[more]

PMID: 36151243

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Project description:Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis, which is characterized by increased bone resorption and inadequate bone formation. As novel antiosteoporotic therapeutics are needed, understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets. This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation. Osteoclasts were differentiated from CD14+ monocytes from eight female donors. RNA sequencing during differentiation revealed 8 980 differentially expressed genes grouped into eight temporal patterns conserved across donors. These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs. Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks. The donor-specific expression patterns revealed genes at the monocyte stage, such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1, encoding LOX-1), that are predictive of the resorptive activity of mature osteoclasts. The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation, and these receptors are associated with bone mineral density SNPs, suggesting that they play a pivotal role in osteoclast differentiation and activity. The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1 (C5AR1), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFAR4/GPR120). Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 decreased the resorptive activity of mature osteoclasts, and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts. In conclusion, we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity. These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

Project description:Several previous reports have suggested that estrogen (E2) is a vital signal responsible for the regulation of skeletal homeostasis and bone remodeling in mammals. E2 could efficiently accelerate the growth of medullary bone in pullets during sexual maturity. Furthermore, the low E2 level can strengthen the mechanical bone functions in female hens. However, mechanistic studies to describe the effects of E2 on bone in pullets during the initiation of the puberty period are remaining elusive. Therefore, the aim of this study was to explore the effect of inhibiting E2 biosynthesis on the biomechanical properties and its molecular mechanism during sexual maturity of pullets. In this study, a total of 90 Hy-line Sonia pullets with comparable body weight at 13 wk of age were selected and categorized into 2 separate groups. Daily, 0.5 mg/4 mL of letrozole (LZ) was orally administered to the treatment (TRT) group and 4 mL of saline to the control (CON) group of pullets for 6 wk. Compared with the CON group, a lower plasma E2 level was observed in the TRT group. Furthermore, plasma P, Gla protein (BGP), and 1,25-dihydroxy vitamin D3 (1,25-(OH)2D3) levels were markedly suppressed, whereas the plasma alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) levels were significantly elevated. Moreover, the cortical bone thickness and breaking strength of the tibia and femur, the bone mineral density of the humerus, and the bone mineral content of the humerus as well as the femur were increased significantly. The expression levels of 340 differentially expressed genes (DEGs) differed significantly between the CON and TRT group in the tibia at 19 wk of age. Among them, 32 genes were up-regulated, whereas 308 were down-regulated in the TRT group. The variations in candidate genes associated with osteoclast differentiation and cell adhesion may indicate that LZ inhibits E2 biosynthesis, consequently, reduces osteoclast differentiation by suppressing inter-cellular communication and cells attaching to extracellular matrix components. Taken together, the present study demonstrated that inhibiting E2 synthesis during sexual maturity of pullets decreased osteoclast differentiation and considerably enhanced bone quality.

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Estrogen regulation of myokines that enhance osteoclast differentiation and activity.

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Estrogen regulation of myokines that enhance osteoclast differentiation and activity.

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