Periapical Lesions & Bisphosphonates Mechanism

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Questions and Answers

Briefly describe the role of collagen in maintaining the structural integrity of bone.

Collagen, specifically type I, provides a flexible framework within bone that resists tensile forces. This prevents the bone from becoming brittle and prone to fracture under stress.

Outline the key steps in the process of periapical lesion formation, starting with the presence of bacterial components.

LPS/LTA in periapical tissue activate macrophages, macrophages present antigens to T-cells, T-cells release pro-inflammatory cytokines, osteoblasts release RANKL, RANKL induces osteoclast formation and activation, osteoclasts resorb bone.

Explain how bisphosphonates inhibit bone resorption at the molecular level, differentiating between simple and nitrogen-containing bisphosphonates.

Simple bisphosphonates are incorporated into ATP analogs, inducing osteoclast apoptosis. Nitrogen-containing bisphosphonates inhibit FPP synthase, disrupting osteoclast function and survival via toxic metabolite synthesis and prevent the synthesis of key lipids.

Describe Martini and Gennari's proposed mechanism by which certain therapies can suppress RANKL-induced bone resorption.

<p>Martini and Gennari proposed that therapies could decrease RANKL production and increase OPG production. This shift in balance suppresses RANKL-induced bone resorption.</p> Signup and view all the answers

Explain how mechanical loading of bone can influence osteoclast activity, according to You and Temiyasathit's research.

<p>Mechanical loading inhibits osteocytes from stimulating osteoclast formation through cell-to-cell contact. It may also induce osteocyte signaling that further inhibits osteoclastogenesis.</p> Signup and view all the answers

How do osteocytes act as mechanosensors in bone, and what is the significance of this function for bone remodeling?

<p>Osteocytes detect mechanical loading in bone and signal to regulate osteoclast and osteoblast activity, adapting bone structure to withstand applied forces and prevent excessive bone resorption.</p> Signup and view all the answers

Explain how the inhibition of FPP synthase by nitrogen-containing bisphosphonates leads to osteoclast inhibition.

<p>Inhibition of FPP synthase disrupts the synthesis of essential isoprenoid lipids required for osteoclast survival and activity, which leads to osteoclast dysfunction and apoptosis.</p> Signup and view all the answers

Describe the dual role of osteoblasts in periapical lesion formation.

<p>Osteoblasts release RANKL, which promotes osteoclast formation and bone resorption, but can also be influenced to release OPG which inhibits bone resorption.</p> Signup and view all the answers

Discuss why understanding the MOA of bisphosphonates is important for long-term patient outcomes.

<p>Important for managing potential side effects like osteonecrosis of the jaw and atypical femoral fractures, by guiding treatment duration and patient selection.</p> Signup and view all the answers

Explain why targeting the RANKL pathway has become a focus in treating bone-resorptive diseases.

<p>RANKL is a key regulator of osteoclast formation and activity. Inhibiting RANKL reduces bone resorption and helps restore bone homeostasis.</p> Signup and view all the answers

Flashcards

Bone Composition

Bone is composed of collagen type I by weight.

Periapical Lesion Formation

LPS/LTA in periapical (PA) tissue are taken up by macrophages (APCs), presented to T-cells, which release pro-inflammatory cytokines. Osteoblasts then release RANKL, inducing osteoclast formation/activation, leading to bone resorption.

Bisphosphonates MOA

Bisphosphonates inhibit osteoclast precursors, recruitment, and activity, and can induce osteoclast apoptosis, decreasing RANKL and increasing OPG, suppressing RANKL-induced bone resorption.

Bisphosphonates Mechanism

Simple bisphosphonates cause osteoclast apoptosis, converting into toxic ATPase analogs; nitrogen-containing bisphosphonates inhibit FPP synthase, leading to toxic metabolite synthesis.

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Osteocytes as Mechanosensors

Mechanical loading of bone inhibits osteocytes' ability to induce osteoclast formation via cell-to-cell contact, potentially through osteocyte signaling that inhibits osteoclastogenesis.

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Study Notes

  • By weight, bone is comprised of type I collagen.

Periapical Lesion Formation

  • Lipopolysaccharides (LPS) and lipoteichoic acid (LTA) in periapical (PA) tissue are absorbed by macrophages, which are antigen-presenting cells (APCs).
  • APCs present the antigens to T-cells
  • T-cells release pro-inflammatory cytokines.
  • Osteoblasts release RANKL (receptor activator of nuclear factor kappa-Î’ ligand).
  • This induces osteoclast formation and activation.
  • Osteoclasts attach to the bone surface.
  • Resorption occurs along the ruffled border of osteoclasts.

Bisphosphonates Mechanism of Action

  • Bisphosphonates inhibit osteoclast precursors.
  • Bisphosphonates inhibit osteoclast recruitment to the bone surface.
  • Bisphosphonates inhibit osteoclast activity.
  • Bisphosphonates induce osteoclast apoptosis.
  • Martini, Gennari: Bisphosphonates decrease RANKL and increase OPG (osteoprotegerin).
  • increased OPG suppresses RANKL-induced bone resorption
  • Rogers: Simple bisphosphonates induce osteoclast apoptosis by converting into a toxic ATPase analog.
  • Nitrogen-containing bisphosphonates inhibit farnesyl pyrophosphate (FPP) synthase.
  • FPP inhibition leads to toxic metabolite synthesis.
  • FPP inhibition causes a loss of key long-chain lipids, needed for osteoclast survival and activity.

Osteocytes as Mechanosensors

  • Mechanical loading of bone inhibits osteocytes from inducing osteoclast formation through cell-to-cell contact (You, Temiyasathit).
  • Mechanical loading induces osteocyte signaling that inhibits osteoclastogenesis.

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