Dodington DW(1), Yumol JL(2), Yang J(1), Pollock-Tahiri E(1), Sivasubramaniyam T(1), Sacco SM(2), Schroer SA(1), Li YE(1), Le H(1), Ward WE(2)(3), Woo M(1)(4)(5). Author information:
(1)Toronto General Hospital Research Institute, University Health Network,
Toronto, Ontario, Canada.
(2)Department of Kinesiology and.
(3)Department of Health Sciences, Brock University, St. Catharines, Ontario,
(4)Institute of Medical Science and Department of Immunology and.
(5)Division of Endocrinology and Metabolism, Department of Medicine, University
Health Network/Sinai Health System, University of Toronto, Toronto, Ontario,
Osteoclasts are specialized cells of the hematopoietic lineage that are responsible for bone resorption and play a critical role in musculoskeletal disease. JAK2 is a key mediator of cytokine and growth factor signaling; however, its role in osteoclasts in vivo has yet to be investigated. To elucidate the role of JAK2 in osteoclasts, we generated an osteoclast-specific JAK2-KO (Oc-JAK2-KO) mouse using the Cre/Lox-P system. Oc-JAK2-KO mice demonstrated marked postnatal growth restriction; however, this was not associated with significant changes in bone density, microarchitecture, or strength, indicating that the observed phenotype was not due to alterations in canonical osteoclast function. Interestingly, Oc-JAK2-KO mice had reduced osteoclast-specific expression of IGF1, suggesting a role for osteoclast-derived IGF1 in determination of body size. To directly assess the role of osteoclast-derived IGF1, we generated an osteoclast-specific IGF1-KO mouse, which showed a similar growth-restricted phenotype. Lastly, overexpression of circulating IGF1 by human transgene rescued the growth defects in Oc-JAK2-KO mice, in keeping with a causal role of IGF1 in these models. Together, our data show a potentially novel role for Oc-JAK2 and IGF1 in the determination of body size, which is independent of osteoclast resorptive function.
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