The role of furin in bone homeostasis

Wei Ming Benjamin Ng

    Research output: ThesisDoctoral Thesis

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    Abstract

    Bone is continuously being reshaped and repaired during adult life by a process termed bone remodelling. This process is tightly regulated by the cellular activities of bone resorbing osteoclasts and bone forming osteoblasts within the bone microenvironment. However, imbalances in either bone resorption or bone formation can often lead to diseases such as osteoporosis, osteopetrosis.

    Furin belongs to a family of highly conserved proprotein convertases, which catalyses the hydrolytic cleavage of a broad range of substrate molecules after basic amino acid residues in the constitutive secretory pathway. Furin is essential for cellular function and implicated in a diverse range of pathophysiological disorders, however, there is limited knowledge regarding the role of furin in bone remodelling. Using comparative microarray and gene annotation analysis between osteoclasts and bone marrow monocyte/macrophages (BMM), and during OB differentiation, furin was uncovered to be abundantly expressed in these bone residing cells. Thus, it is hypothesized that furin plays an important role in the regulation of bone remodelling and homeostasis.

    The global deletion of furin leads to embryonic lethality precluding investigations of its role in postnatal bone. To address the physiological role of furin in osteoclast biology, mice specifically lacking furin in mature osteoclasts (FurinΔOC) were generated and the bone phenotype was assessed. MicroCT and histomorphometric analyses of female FurinΔOC mice demonstrated a significant increase in trabecular bone mass due to a reduction in osteoclast numbers and bone resorption in vivo. In contrast, cortical bone mass was not altered in FurinΔOC mice. Furthermore, neither the targeted deletion nor the pharmacological inhibition of furin significantly altered mature osteoclast formation in vitro. However, in vitro mechanistic studies revealed that furin is essential for osteoclastic bone resorption and acidification via its role as the primary processing enzyme of the V-ATPase proton pump subunit Ac45.

    To address the physiological role of furin in mature osteoblasts, mice specifically lacking furin in mature osteoclasts (FurinΔOB) were generated and the bone phenotype was assessed. Similar to FurinΔOC mice, microCT histomorphometric analyses of male FurinΔOB mice revealed a significant increase in trabecular bone mass as a result of a reduction in osteoclast numbers and bone resorption in vivo. By contrast, cortical bone mass was reduced in these mice. Furthermore, in vitro studies revealed that targeted deletion of furin in osteoblasts impaired bone mineralization and osteoclast formation. However the exact molecular mechanisms by which the specific loss of furin in osteoblasts causes an increase in bone mass remains to be elucidated. Collectively, furin regulates the osteoclast acidification machinery, in part through the activation of Ac45, and hence, serves as a positive regulator of osteoclast-mediated bone resorption. Whereas, furin activity in osteoblasts differentially regulates trabecular and cortical bone mass in vivo, and promotes mineralization and osteoclast formation in vitro. Thus, furin is a previously undescribed key regulator of bone homeostasis and may serve as a potential therapeutic target for the treatment of osteolytic diseases.

    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2015

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