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Endogenous Prostaglandin E 2 and Insulin‐like Growth Factor 1 Can Modulate the Levels of Parathyroid Hormone Receptor in Human Osteoarthritic Osteoblasts
Author(s) -
Hilal George,
Massicotte Frédéric,
MartelPelletier Johanne,
Fernandes Julio C.,
Pelletier JeanPierre,
Lajeunesse Daniel
Publication year - 2001
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2001.16.4.713
Subject(s) - medicine , endocrinology , parathyroid hormone , pertussis toxin , parathyroid hormone receptor , cholera toxin , chemistry , receptor , prostaglandin e2 , biology , hormone receptor , g protein , calcium , cancer , breast cancer
Subchondral bone sclerosis may be important for the onset and/or progression of cartilage loss/damage in human osteoarthritis (OA). OA osteoblasts are resistant to parathyroid hormone (PTH) stimulation, which could explain bone sclerosis via the inhibition of PTH‐dependent catabolism. Here, we investigated the molecular mechanism(s) responsible for reduced PTH‐dependent cyclic adenosine monophosphate (cAMP) synthesis in OA subchondral osteoblasts. Although cholera toxin (CTX) increased basal cAMP formation in these cells, it failed to stimulate PTH‐dependent cAMP synthesis, whereas pertussis toxin (PTX) did not inhibit basal cAMP, yet diminished PTH‐dependent cAMP production. Binding of 125 I‐PTH indicated lower PTH receptor levels in OA than in normal osteoblasts (−50.5 ± 9.5%). This could be attributed to either reduced expression of the PTH receptor (PTH‐R) or altered recycling of existing pools of receptors. Reverse‐transcription polymerase chain reaction (RT‐PCR) analysis indicated decreased PTH‐R messenger RNA (mRNA) levels in OA cells that were highly variable (ranging from −10% to −60%), a situation that reflects disease severity. Interestingly, OA osteoblasts produced more prostaglandin E 2 (PGE 2 ) than normal osteoblasts, and using naproxen, a cyclo‐oxygenase inhibitor, increased PTH‐dependent cAMP formation to a level similar to normal osteoblasts. Because heterologous desensitization can explain a decrease in PTH binding but cannot account for reduced PTH‐R expression, we looked at the possible effect of insulin‐like growth factor 1 (IGF‐1) on this parameter. Blocking IGF‐1 signaling with a neutralizing receptor antibody increased 125 I‐PTH binding in both normal and OA osteoblasts. Conversely, treatments with IGF‐1 receptor (IGF‐1R) antibody only slightly increased the levels of PTH‐R mRNA whereas the addition of IGF‐1 significantly reduced PTH‐R mRNA levels (−24.1 ± 7.1%), yet neither PGE 2 nor naproxen modified PTH‐R levels. These results suggest that both IGF‐1 signaling and PGE 2 formation repress PTH‐dependent response in OA osteoblasts, a situation that can contribute to abnormal bone remodeling and bone sclerosis in OA.