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In order to be able to follow IGF-1 pathways, the team used a special line of dwarf laboratory rats that do not produce their own growth hormone. Half the animals in both the tethered and untethered groups were given IGF-1, while all rats in both groups were injected with a compound that traces actively dividing cells. At the end of the trial period, the team found that the numbers of precursor bone cells in the forelimbs of rats that had received IGF-1 was double that of rats that had not received the growth factor. But in the "unloaded" hind limbs, cell division was virtually stalled, regardless of whether animals had received the growth factor or not.

The team then cultured cells from loaded and unloaded bones and put the cells through numerous biochemical assays looking for the point in the bone formation pathway that is blocked when bones are unloaded. They found that while IGF-I bound normally to its receptor, activation of the receptor did not take place. This activation is required for IGF-I to stimulate cells to grow. Bikle and his team then found that this same inhibition of the ability of IGF-I to activate its receptor could be duplicated by inhibiting integrin function. This fit neatly into their observation that integrin levels were reduced by skeletal unloading, These observations link the loss of integrins to the failure of IGF-I to activate its receptor.

"The next step," Bikle says, "is to determine what's impeding production of integrin during skeletal unloading, and what the mechanism is that links the integrin signaling pathway to the IGF-I receptor activation. Once we understand these processes, we'll have some targets that we can address to help us devise interventions to prevent bone loss from skeletal unloading." Based on his c
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Contact: Liese Greensfelder
lgreensfelder@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
23-Feb-2004