Pcsk9 Knockout Aggravated Experimental Apical Periodontitis via LDLR

Area of Science:

• Oral Biology
• Immunology
• Biochemistry

Background:

• Apical periodontitis (AP) is an inflammatory condition affecting the tooth root apex, typically caused by dental pulp infection.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to regulate cholesterol homeostasis and has been implicated in chronic periodontitis.
• The specific role of PCSK9 in the pathogenesis of apical periodontitis remains largely unexplored.

Purpose of the Study:

• To investigate the role of PCSK9 in the development and progression of apical periodontitis.
• To elucidate the molecular mechanisms underlying PCSK9's involvement in AP, particularly its relationship with inflammation and bone resorption.
• To determine if PCSK9 influences osteoclastogenesis in the context of AP.

Main Methods:

• Utilized Pcsk9 knockout (Pcsk9^-/-) mice and wild-type (WT) littermates to model AP.
• Employed micro-computed tomography (micro-CT) and histological staining for assessing periapical bone loss and inflammation.
• Conducted immunofluorescence staining, quantitative real-time polymerase chain reaction (qRT-PCR), and in vitro assays using bone marrow macrophages (BMMs) challenged with lipopolysaccharide (LPS) to evaluate inflammatory markers and osteoclast differentiation.
• Investigated the role of low-density lipoprotein receptor (LDLR) by using Ldlr small interfering RNA (siRNA).

Main Results:

• Pcsk9^-/- mice exhibited significantly greater periapical bone loss and elevated expression of inflammatory factors (TNF-α, IL-6) compared to WT mice.
• PCSK9 expression increased in macrophages upon LPS challenge, and its absence exacerbated LPS-induced inflammation (TNF-α, IL-1β, IL-6).
• PCSK9 deficiency led to increased osteoclast numbers and size, a process dependent on LDLR, with elevated LDLR expression observed in Pcsk9^-/- periapical lesions.

Conclusions:

• PCSK9 deficiency exacerbates the inflammatory response in experimental apical periodontitis.
• Absence of PCSK9 promotes osteoclastogenesis in AP, a process mediated through the low-density lipoprotein receptor (LDLR).
• These findings suggest PCSK9 plays a protective role in apical periodontitis by modulating inflammation and bone resorption via LDLR signaling.