Abstract
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.
Highlights
Osteoclasts are specialized cells of the hematopoietic lineage and mostly known for their function in bone resorption [1]
We found that Oc-Janus kinase 2 (JAK2)–KO mice had marked postnatal growth restriction; this was not associated with significant changes in bone mineral density (BMD), bone microarchitecture, bone strength, osteoclast number, or osteoclastic gene expression, suggesting that osteoclast JAK2 modulates body size without altering the balance between bone formation and bone resorption
Previous studies have hinted at a potential role for JAK2 in osteoclast biology, since cytokines and growth factors that signal through JAK2 have been reported to modulate osteoclastogenesis [23]
Summary
Osteoclasts are specialized cells of the hematopoietic lineage and mostly known for their function in bone resorption [1]. There is some evidence to suggest a role for JAK2 in osteoclast biology. Osteoclasts derived from individuals with myelofibrosis harboring JAK2 activating mutations have impaired osteolytic capacity, implicating JAK2 with osteoclast dysfunction [9]. In vitro studies using JAK2 inhibitors have highlighted a potential role for JAK2 in osteoclasts. Osteoblast/osteoclast cocultures treated with the JAK1/2 inhibitor baricitinib showed decreased osteoclastogenesis due to reduced RANKL expression in osteoblasts [10]. Use of the JAK2 inhibitor AG490 in purified osteoclast cultures inhibited osteoclast apoptosis in response to RANKL withdrawal [11]. Despite these data, the role of osteoclast JAK2 in vivo has yet to be investigated
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