Original Full Length ArticleTransforming growth factor beta 1 induces CXCL16 and leukemia inhibitory factor expression in osteoclasts to modulate migration of osteoblast progenitors

- TGF-β stimulates osteoclasts to increase production of the chemokine CXCL16, which promotes osteoblast migration.
- TGF-β stimulation of CXCL16 is Smad-dependent.
- TGF-β stimulates osteoclasts to increase LIF production, which blocks direct TGF-β stimulation of osteoblast migration.
- TGF-β stimulation of LIF is MEK and Smad-dependent.

The processes of bone resorption and bone formation are tightly coupled in young adults, which is crucial to maintenance of bone integrity. We have documented that osteoclasts secrete chemotactic agents to recruit osteoblast lineage cells, contributing to coupling. Bone formation subsequent to bone resorption becomes uncoupled with aging, resulting in significant bone loss. During bone resorption, osteoclasts release and activate transforming growth factor beta 1 (TGF-β1) from the bone matrix; thus, elevated bone resorption increases the level of active TGF-β in the local environment during aging. In this study, we examined the influences of TGF-β1 on the ability of osteoclasts to recruit osteoblasts. TGF-β1 increased osteoclast expression of the chemokine CXCL16 to promote osteoblast migration. TGF-β1 also directly stimulated osteoblast migration; however, this direct response was blocked by conditioned medium from TGF-β1-treated osteoclasts due to the presence of leukemia inhibitory factor (LIF) in the medium. CXCL16 and LIF expression was dependent on TGF-β1 activation of Smad2 and Smad3. These results establish that TGF-β1 induces CXCL16 and LIF production in osteoclasts, which modulate recruitment of osteoblasts to restore the bone lost during the resorptive phase of bone turnover.