Transcriptional Regulation of Osteoclastogenesis: The Emerging Role of KLF2

Abstract

Dysregulation of osteoclastic differentiation and its activity is a hallmark of various musculoskeletal disease states. In this review, the complex molecular factors underlying osteoclastic differentiation and function are evaluated. The emerging role of KLF2 in regulation of osteoclastic differentiation is examined, specifically in the context of rheumatoid arthritis in which it has been most extensively studied among the musculoskeletal diseases. The therapies that exist to manage diseases associated with osteoclastogenesis are numerous and diverse. They are varied in their mechanisms of action and in the outcomes they produce. For this review, therapies targeting osteoclasts will be emphasized, though it should be noted that many therapies exist which bolster the action of osteoblasts. A new targeted molecular approach is under investigation for the future potential therapeutic development of rheumatoid arthritis.

Keywords: KLF2; differentiation; osteoclasts; rheumatoid arthritis; transcriptional regulation.

Figure 1

M-CSF signaling is critical for the survival, proliferation, and differentiation of early osteoclastic precursor cells. M-CSF binds to the cell surface receptor c-fms, a tyrosine kinase receptor. Intracellular signaling via the MEK/ERK and PI3 Kinase (PI3K) signaling pathways promote cell proliferation. Signaling via PLC increases intracellular glucose (glc), which increases levels of the anti-apoptotic protein Bcl-X(L), leading to cell survival. Adapted from Stanley and Chitu, Cold Spring Harb Perspect Biol, 2014 (37).

Figure 2

RANK/RANKL signaling is critical for osteoclastic differentiation and function. RANKL binding to RANK expressed on the cell surface of preosteoblastic cells activates intracellular adaptor protein TRAF6. Activation of c-fos and NF-κB pathways induces the NFATc1 gene. Moreover, activation of PLCγ increases intracellular calcium concentrations; this activates the protein calceineurin, which leads to recruitment of NFATc1 to its own promoter which further induces NFATc1. RANK signaling inhibits the anti-osteoclastic genes interferon regulatory factor 8 (IRF8), V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MafB), inhibitors of differentiation (Ids), and LIM homeobox 2 (Lhx2), which inhibit NFATc1 expression. Adapted from Kim and Kim, J Bone Metab, 2014 (45).

Figure 3

KLF2 attenuates osteoclastogenesis via several complementary mechanisms. KLF2 plays a role in epigenetic modulation of the pro-osteoclastogenic molecule MMP9; data from our lab show that KLF2 knockdown significantly increased enrichment of the active histone marks H3K9Ac and H4K8Ac and respective histone acetylase transfer (HAT) enzymes P300 and PCAF at the enrichment sites for the MMP9 gene (80). KLF2 inhibits pro-inflammatory markers, thereby further inhibiting monocytic activation (72). Furthermore, KLF2 promotes cell quiescence, decreasing osteoclastic activation and function. Altogether, its effects prevent excessive osteoclastic activity, slowing RA disease progression.

Figure 4

The emerging role of KLF2 in osteoclastic regulation. Osteoclastic differentiation from myeloid precursor cells is critically regulated by M-CSF and RANKL (2). KLF2 may play an inhibitory role at several stages of osteoclastic differentiation, maturation, and activation (72).