9 research outputs found
ACVR2B/Fc counteracts chemotherapy-induced loss of muscle and bone mass
Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer
ÎČ-aminoisobutyric Acid, l-BAIBA, Is a Muscle-Derived Osteocyte Survival Factor
Summary: Exercise has beneficial effects on metabolism and on tissues. The exercise-induced muscle factor ÎČ-aminoisobutyric acid (BAIBA) plays a critical role in the browning of white fat and in insulin resistance. Here we show another function for BAIBA, that of a bone-protective factor that prevents osteocyte cell death induced by reactive oxygen species (ROS). l-BAIBA was as or more protective than estrogen or N-acetyl cysteine, signaling through the Mas-Related G Protein-Coupled Receptor Type D (MRGPRD) to prevent the breakdown of mitochondria due to ROS. BAIBA supplied in drinking water prevented bone loss and loss of muscle function in the murine hindlimb unloading model, a model of osteocyte apoptosis. The protective effect of BAIBA was lost with age, not due to loss of the muscle capacity to produce BAIBA but likely to reduced Mrgprd expression with aging. This has implications for understanding the attenuated effect of exercise on bone with aging
Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia
Abstract Background Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally underâstudied in OC due to a limited number of preâclinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. Methods Nod SCID gamma mice (n = 6â10) were injected intraperitoneally with 1 Ă 107 ESâ2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumourâderived effects on muscle fibres were investigated in C2C12 myotube cultures. ILâ6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. Results In about 2 weeks, ESâ2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ESâ2 tumours caused severe cachexia with marked loss of body weight (â12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumourâbearing mice (approximately â35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle crossâsectional area (â34%, P < 0.01) and muscle weakness (â50%, P < 0.001). Body composition assessment by dualâenergy Xâray absorptiometry revealed decreased bone mineral density (â8%, P < 0.01) and bone mineral content (â19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by microâCT imaging of bone morphometry. In the ESâ2 mouse model, cachexia was also associated with high tumourâderived ILâ6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phosphoâSTAT3 (+274%, P < 0.001), reduced phosphoâAKT (â44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ESâ2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (â16%, P < 0.001), consistent with elevated phosphoâSTAT3 (+1.4âfold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the ILâ6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. Conclusions Our results suggest that the development of ESâ2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated ILâ6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC
Stat3 in osteocytes mediates osteogenic response to loading
Signal transducer and activator of transcription 3 (Stat3) is a member of the Stat family of proteins involved in signaling in many different cell types, including osteocytes. Osteocytes are considered major mechanosensing cells in bone due to their intricate dendritic networks able to sense changes in physical force and to orchestrate the response of osteoclasts and osteoblasts. We examined the role of Stat3 in osteocytes by generating mice lacking Stat3 in these cells using the Dmp-1(8kb)-Cre promoter (Stat3cKO mice). Compared to age-matched littermate controls, Stat3cKO mice of either sex (18âŻweeks old) exhibit reduced bone formation indices, decreased osteoblasts and increased osteoclasts, and altered material properties, without detectable changes in bone mineral density (BMD) or content of either trabecular or cortical bone. In addition, Stat3cKO mice of either sex show significantly decreased load-induced bone formation. Furthermore, pharmacologic inhibition of Stat3 in osteocytes in vitro with WP1066 blocked the increase in cytosolic calcium induced by ATP, a mediator of the cellular responses to sheer stress. WP1066 also increased reactive oxygen species (ROS) production in cultured MLO-Y4 osteocytes. These data demonstrate that Stat3 is a critical mediator of mechanical signals received by osteocytes and suggest that osteocytic Stat3 is a potential therapeutic target to stimulate bone anabolism
Characterization of a novel murine Sost ERT2 Cre model targeting osteocytes
Animal model: Transgenic mice offer platform to study mature osteocytes A new transgenic mouse allows DNA modifications to be targeted to mature bone cells known as osteocytes, enabling researchers to better study the function of this cell population, although the model has some weaknesses that may restrict its use. Lynda Bonewald from Indiana University, Indianapolis, USA, and colleagues engineered mice to express introduced genetic material only in cells in which a gene called Sost is normally active â namely, osteocytes â and only when experimenters introduce a drug called tamoxifen. In general, transgene activity was contained to the osteocytes, but a full characterization of the mice showed some issues. For one, spontaneously transgene expression occurred in older mice in the absence of tamoxifen, although this was limited to the mature bone cells. With tamoxifen, the researchers observed some transgene expression outside of the bone. Most problematically, there were some broad muscle defects