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Nitric oxide regulation of cGMP production in osteoclasts
S S Dong1, J P Williams, S E Jordan
1Department of Pathology, University of Alabama at Birmingham, 35294-0007, USA.
Abstract:
Bone resorption by osteoclasts is modified by agents that affect cyclic guanosine monophosphate (cGMP), but their relative physiological roles, and what components of the process are present in osteoclasts or require accessory cells such as osteoblasts, are unclear. We studied cGMP regulation in avian osteoclasts, and in particular the roles of nitric oxide and natriuretic peptides, to clarify the mechanisms involved. C-type natriuretic peptide drives a membrane guanylate cyclase, and increased cGMP production in mixed bone cells. However, C-type natriuretic peptide did not increase cGMP in purified osteoclasts. By contrast, osteoclasts did produce cGMP in response to nitric oxide (NO) generators, sodium nitroprusside or 1-hydroxy-2-oxo-3,3-bis(3-aminoethyl)-1-triazene. These findings indicate that C-type natriuretic peptide and NO modulate cGMP in different types of bone cells. The activity of the osteoclast centers on HCI secretion that dissolves bone mineral, and both NO generators and hydrolysis-resistant cGMP analogues reduced bone degradation, while cGMP antagonists increased activity. NO synthase agonists did not affect activity, arguing against autocrine NO production. Osteoclasts express NO-activated guanylate cyclase and cGMP-dependent protein kinase (G-kinase). G-kinase reduced membrane HCI transport activity in a concentration-dependent manner, and phosphorylated a 60-kD osteoclast membrane protein, which immunoprecipitation showed is not an H+-ATPase subunit. We conclude that cGMP is a negative regulator of osteoclast activity. cGMP is produced in response to NO made by other cells, but not in response to C-type natriuretic peptide. G-kinase modulates osteoclast membrane HCI transport via intermediate protein(s) and may mediate cGMP effects in osteoclasts.
Insights
Cyclic guanosine monophosphate (cGMP) negatively regulates osteoclast activity by inhibiting acid secretion. Nitric oxide (NO) stimulates cGMP production in osteoclasts, impacting bone resorption.
Area of Science:
- Cell Biology
- Bone Physiology
- Biochemistry
Background:
- Osteoclast-mediated bone resorption is crucial for skeletal homeostasis.
- Cyclic guanosine monophosphate (cGMP) is implicated in regulating bone resorption, but its precise role and cellular sources remain unclear.
- The involvement of nitric oxide (NO) and natriuretic peptides in cGMP-mediated osteoclast regulation requires further investigation.
Purpose of the Study:
- To elucidate the mechanisms of cGMP regulation in avian osteoclasts.
- To determine the specific roles of nitric oxide (NO) and natriuretic peptides in modulating osteoclast activity via cGMP.
- To identify the cellular components and signaling pathways involved in cGMP-dependent regulation of bone resorption.
Main Methods:
- Investigated cGMP production in purified avian osteoclasts and mixed bone cells in response to C-type natriuretic peptide and NO generators.
- Assessed the effects of NO generators, cGMP analogues, and cGMP antagonists on osteoclast bone degradation.
- Examined the expression and activity of NO-activated guanylate cyclase and cGMP-dependent protein kinase (G-kinase) in osteoclasts.
- Identified G-kinase substrates through phosphorylation assays and immunoprecipitation.
Main Results:
- C-type natriuretic peptide increased cGMP in mixed bone cells but not in purified osteoclasts.
- Nitric oxide (NO) generators significantly increased cGMP production in purified osteoclasts.
- Both NO generators and hydrolysis-resistant cGMP analogues reduced osteoclast-mediated bone degradation, while cGMP antagonists enhanced it.
- Osteoclasts express functional NO-activated guanylate cyclase and G-kinase, which phosphorylates a 60-kD membrane protein, inhibiting HCl transport.
Conclusions:
- cGMP acts as a negative regulator of osteoclast activity, primarily by inhibiting membrane HCl transport.
- Osteoclast cGMP is stimulated by NO, likely produced by accessory cells, rather than by C-type natriuretic peptide.
- G-kinase mediates the inhibitory effects of cGMP on osteoclast function through phosphorylation of specific membrane proteins, distinct from H+-ATPase subunits.
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