Growth without growth hormone: can growth and differentiation factor 5 be the mediator?

Growth without growth hormone (GH) is often observed in the setup of obesity; however, the missing link between adipocytes and linear growth was until now not identified. 3T3L1 cells were induced to differentiate into adipocytes and their conditioned medium (CM) (adipocytes CM, CMA) was added to metatarsals bone culture and compared to CM derived from undifferentiated cells. CMA significantly increased metatarsals bone elongation. Adipogenic differentiation increased the expression of growth and differentiation factor (GDF)-5, also found to be secreted into the CMA. GDF-5 significantly increased metatarsal length in culture; treatment of the CMA with anti-GDF-5 antibody significantly reduced the stimulatory effect on bone length. The presence of GDF-5 receptor (bone morphogenetic protein receptor; BMPR1) in metatarsal bone was confirmed by immunohistochemistry. Animal studies in rodents subjected to food restriction followed by re-feeding showed an increase in GDF-5 serum levels concomitant with nutritional induced catch up growth. These results show that adipocytes may stimulate bone growth and suggest an additional explanation to the growth without GH phenomenon.