
We identified osteoclast-derived SLIT3 as a new coupling factor using fractionated secretomics. Coupling links bone resorption to bone formation. SLIT3 stimulated the recruitment and proliferation of osteoblasts into bone remodeling sites via activation of β-catenin. Autocrine signaling by SLIT3 also inhibited bone resorption by suppressing the fusion and differentiation of pre-osteoclasts. All mice lacking
Bone remodeling entails constant replacement of old bone by new bone under normal conditions. Coupling, the process of osteoclastic bone resorption followed by osteoblastic bone formation, occurs during bone remodeling. Its imbalance leads to metabolic bone diseases such as osteoporosis. Coupling also limits the therapeutic efficacy of antiresorptive agents including most of the anti-osteoporotic medications, because these agents suppress bone formation as well as bone resorption. Their long-term adverse effects, such as osteonecrosis of the jaw, atypical femur fracture, and delayed bone fracture healing, occur as a result of coupling, because of inadequate new bone formation. Bone anabolic agents exhibit limited therapeutic efficacy under conditions of suppressed bone resorption, because coupling factors may be depleted in these conditions.
Therefore, it is important to discover a coupling factor, which acts as a bone anabolic factor even in conditions of suppressed bone resorption. To date, several coupling factors have been identified, and are categorized into 2 classes according to their origin (Takeshita S et al. (2013) J Clin Invest 123, 3914–3924). One class includes factors derived from the bone matrix during bone resorption, such as transforming growth factor β and insulin-like growth factor 1. The other class comprises factors derived from the osteoclasts such as sphingosine-1-phosphate, WNT10B, bone morphogenetic protein 6, and collagen triple helix repeat containing 1. Currently, it is regarded that osteoclasts are the major source of coupling factors. Their functions have been identified in clinical trials investigating antiresorptives and findings of our
We performed fractionated secretomics to identify molecules that stimulate osteoblastic migration from osteoclasts, and selected a candidate based on three criteria. First, its expression should be higher in mature osteoclasts than in immature cells. Second, it should stimulate osteoblastic migration. Lastly, osteoblastic migration stimulated by an osteoclast-conditioned medium should be abrogated by the suppression of specific factors in osteoclasts. Only SLIT3 completely satisfied all these 3 criteria. SLIT were originally discovered as a chemorepellent that controls axon crossing in the midline of the brain, and occurs in 3 isoforms (SLIT1–3) (Blockus H and Chédotal A (2016) Development 143, 3037–3044). Their receptors manifest 4 isoforms (ROBO1–4).
NFκB p50 and CREB activated during osteoclastic differentiation, directly binded to the promoter region of
From a therapeutic perspective, SLIT3 may be an ideal target because of its dual actions on bone formation and resorption. To confirm its clinical relevance, we performed clinical studies in postmenopausal women. A next-generation sequencing study has shown that only 1
The large size of human SLIT3 (approximately 170 kDa) may interfere with drug development. It is known that the shorter fragment of SLIT3, i.e., SLIT3 LRRD2 binds to its receptor (Howitt JA et al (2004) EMBO J 23, 4406–4412). With an efficacy and mode similar to that of the whole SLIT3, the human SLIT3 LRRD2 stimulated osteoblastic migration and proliferation, and suppressed osteoclast formation. Its intravenous injections protected ovariectomized mice from bone loss. However, frequent injections of LRRD2 are needed for sufficient treatment efficacy
In conclusion, the results of our
The present report was supported by grants from the Korea Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI13C1634 and HI15C0377) and from Asan Institute for Life Sciences, Seoul, Republic of Korea (2015-347).
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