Endogenous Prostaglandin E2 and Insulin-like Growth Factor 1 Can Modulate the Levels of Parathyroid Hormone Receptor in Human Osteoarthritic Osteoblasts

Abstract

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. Reversetranscription 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.

Altered mineralization of human osteoarthritic osteoblasts is attributable to abnormal type I collagen production

“…Tibial plateaus were obtained from patients with OA who were undergoing total knee replacement surgery and the tissue samples were prepared as previously described (1,(14)(15)(16). The study group comprised 84 patients (34 men and 50 women; mean Ϯ SD age 70.3 Ϯ 8.5 years), all of whom had OA according to the recognized clinical criteria of the American College of Rheumatology (23).…”

“…Our group (1,(13)(14)(15)(16) and other investigators (17,18) previously showed that osteoblasts from OA patients are abnormal and show altered phenotypic characteristics. Moreover, OA osteoblasts may produce factor(s) that can promote glycosaminoglycan release from normal cartilage in vitro (3,17) or down-regulate aggrecan from chondrocytes (18).…”

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

“…OA subchondral bone osteoblasts were shown to produce less cAMP in response to parathyroid hormone (PTH) stimulation [37], and they have fewer PTH receptors [82]. Since PTH is a negative regulator of collagen synthesis, this could then lead to altered type I collagen production in OA bone tissue [83,84].…”

Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone

“…It is speculated that subchondral bone remodeling is linked to cartilage degradation, not only by modifying the mechanical properties of the subchondral bone (9) but also by releasing factors that may influence cartilage metabolism (10,11). Thus, the understanding of the mechanisms leading to bone sclerosis is of the utmost importance in the treatment of OA.Indeed, previous studies have demonstrated that some osteoblasts are phenotypically different and may produce increased levels of alkaline phosphatase (AP), osteocalcin (OC), transforming growth factor ␤1 (TGF␤1), insulin-like growth factor 1 (IGF-1), and urokinase plasminogen activator, while levels of IGF binding proteins 3, 4, and 5 are lower and plasminogen activator inhibitor 1 and interleukin-1␤ (IL-1␤) levels remain unchanged (12)(13)(14)(15). Because it is a potent stimulator of bone matrix formation by osteoblasts, the local…”

“…Because it is a potent stimulator of bone matrix formation by osteoblasts, the local accumulation of free IGF-1 is described as a key feature of bone sclerosis in OA (12). OA osteoblasts are resistant to parathyroid hormone (PTH) stimulation, a characteristic that can also contribute to abnormal bone remodeling and bone sclerosis in OA (12). Moreover, OA osteoblasts produce an abnormal homotrimeric type I collagen, responsible for the low mineralization of OA subchondral bone (16,17).…”