Abstract

The adult skeleton undergoes bone remodeling that consists of bone formation by osteoblasts and bone resorption by osteoclasts. When the amount of bone resorbed is greater than the amount of new bone formed, low bone mass results, putting individuals at increased risk for osteoporosis and osteoporotic bone fracture. Nitrogenous bisphosphonates (NBPs) are the most common first line treatment for conditions of low bone mass. NBPs reduce osteoclast bone resorption by impairing the post-translational modification of small GTPases. Small GTPases play crucial roles in the differentiation, function, and survival of osteoclasts. Understanding the roles of individual small GTPases in osteoclast biology may lead to more targeted therapies for the treatment of low bone mass. In this review, we discuss recent investigations into the in vivo effects of individual GTPase deletion in osteoclasts and the molecular roles for small GTPases in osteoclast biology.

Highlights

  • The adult skeleton undergoes bone remodeling that consists of bone resorption by osteoclasts and subsequent bone formation by osteoblasts

  • The significance of small GTPases in osteoclast biology came to light when it was discovered that the effect of nitrogenous bisphosphonates (NBPs) to inhibit bone resorption occurred through impaired protein prenylation [15,16]

  • The results of these in vivo studies demonstrate that targeting the activities of certain GTPases decreases bone resorption and increases bone mass without decreasing osteoclast number; specific targeting of these GTPases in conditions of low bone mass could lead to improved bone formation compared to NBP treatment

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Summary

Introduction

The adult skeleton undergoes bone remodeling that consists of bone resorption by osteoclasts and subsequent bone formation by osteoblasts. NBPs reduce bone resorption by inhibiting an enzyme required for the post-translational modification of small GTPases in osteoclasts [3]. The effectiveness of NBP therapy supports that understanding how small GTPases are modified and their mechanisms of action in regulation of osteoclast function may promote the development of more targeted therapies to suppress bone resorption while preserving the anabolic effects of osteoclasts on osteoblasts. By inhibiting enzymes within this pathway, cells can be depleted of these and other isoprenoid metabolites, leading to impaired protein prenylation. The significance of small GTPases in osteoclast biology came to light when it was discovered that the effect of NBPs to inhibit bone resorption occurred through impaired protein prenylation [15,16]. GGPP, as well as other downstream isoprenoid metabolites The depletion of these groups impairs the prenylation of GTPases, preventing their membrane localization. Disrupted prenylation of GTPases results in inappropriate signaling, suppressing osteoclast differentiation and function and stimulating apoptosis [17]

In vivo effects of osteoclast small GTPase deletion
Functions of small GTPases in osteoclast biology
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