Growth Hormone Improves Growth Retardation Induced by Rapamycin without Blocking Its Antiproliferative and Antiangiogenic Effects on Rat Growth Plate

Abstract

Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis.

Lithium Chloride Dependent Glycogen Synthase Kinase 3 Inactivation Links Oxidative DNA Damage, Hypertrophy and Senescence in Human Articular Chondrocytes and Reproduces Chondrocyte Phenotype of Obese Osteoarthritis Patients

“…Since LiCl is able to activate the PI3K/-Akt pathway and to inhibit GSK3β [ 30 , 35 ], it can be considered as a mimicker of insulin or other growth factors or inflammatory cytokines that lead to GSK3β inactivation as a result of PKC/PI3K/Akt activation [ 36 , 37 ], whereas the comparison with SB216763 and GSK3β silencing strategies can help in distinguishing the effects which are uniquely dependent on GSK3β inactivation versus those which are instead dependent on other signaling molecules.…”

mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy

“…Unlike what we observed in Rpt +/-mice, we found that rapamycin administration inhibited bone growth in control mice, suggesting that the systemic administration of rapamycin may have altered additional pathways that are converging on bone growth, consistent with previously published results (Supplemental Figure 6, A and B and ref. 32).…”

Mammalian target of rapamycin as a therapeutic target in osteoporosis

“…Additionally, mTOR signaling can also regulate other cells which play role in skeletogenesis. Reportedly, rapamycin reduces the proliferation of chondrocytes, endotheliocytes, and periosteum cells, destroy mature and hypertrophic chondrocytes, and inhibits vasculogenesis of chondrocytes (Alvarez‐Garcia et al, 2010; Álvarez‐García et al, , ; Holstein et al, ; Sanchez & He, ). Interestingly, bafilomycin A1 and chloroquine (both are inhibitors of autophagy) are found to activate mTORC1 signaling in autophagy‐independent manner unexpectedly, which is observed exclusively in chondrocytes but not in osteoblasts, fibroblasts, or liver cells (Newton, Vuppalapati, Bouderlique, & Chagin, ).…”

“…On the basis of previous numerous types of clinical evidences (Bruyn et al, 2008;Lai et al, 2012;Su et al, 2009) Several basic studies reveal that rapamycin can suppress the growth of body weight, alter the normal structure and dynamic equilibrium of growth plate, retard the growth of long bone, and influence fracture healing of femur (Álvarez-García et al, 2007(Álvarez-García et al, , 2010(Álvarez-García et al, , 2012Holstein et al, 2008;Phornphutkul et al, 2009;Sanchez & He, 2009;Yang et al, 2015). Recently, anticancer synergy with the use of mTOR signaling inhibitors have been postulated in osteosarcoma treatment, suggesting that mTOR inhibition may also have a positive impact on bone (Moriceau et al, 2010).…”