Abnormal osteoblasts may be initial step in OA

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Rheumawire

Jan 6, 2004

Abnormal osteoblasts may be initial step in OA

Montreal, QC - Subchondral bone changes precede osteoarthritis (OA)

cartilage degeneration as OA develops and are partly due to abnormal

osteoblast function, Dr Lajeunesse (Centre Hospitalier de

l'Université de Montréal, QC) reports in Osteoarthritis and Cartilage

[1].

" Our main working hypothesis is that an underlying bone-cell defect is

responsible for the observed cartilage damage in osteoarthritis, "

Lajeunesse tells rheumawire. His group has found that OA bone tissue is

sclerotic and undermineralized and that enhanced bone remodeling by

abnormal osteoblasts may trigger cartilage damage and overwhelm the

body's attempts at cartilage repair.

" The exact role played by cytokines and prostaglandins remains

controversial. However, restraining collagen deposition and mineral

removal and/or improving mineral deposition could provide a better, more

mineralized bone matrix in OA patients, " Lajeunesse says. " Since bone

tissue is undermineralized in osteoarthritis yet sclerotic, we have to

think about either slowing mineral removal with bisphosphonates or

improving bone-mineral deposition and new bone formation, with

intermittent parathyroid hormone [PTH] treatment, for example. "

Clinical studies have shown increases in the indices of both bone

resorption and bone formation in OA patients. Studies using bone

explants from OA patients have shown that these contain more collagen

type I, transforming growth factor beta (TGF-), insulinlike growth

factor 1 (IGF-1), and IGF-2 than normal bone tissues but have less

mineral and similar levels of collagen cross-links.

Lajeunesse points out that bone tissues are abnormal in OA patients even

at sites distant from weight-bearing joints. Bone sclerosis has been

assumed to be the secondary to cartilage breakdown, but Lajeunesse says

that studies in animals such as macaque and guinea pig, which naturally

develop OA, show that the bone changes begin before the cartilage

damage.

Lajeunesse thinks that enhanced bone remodeling is the initiating event

for cartilage damage and that attempts to repair the cartilage cause

many characteristic changes in OA bone and cartilage. In bone, this

includes changes in IGF-1, IGF binding proteins (IGFPBs), and TGF-, as

well as alterations in the urokinase plasminogen activator (uPA)/plasmin

system. In OA cartilage there are changes in IGF-1-binding-protein

levels and in the uPA/plasmin system.

Lajeunesse's group set out to determine whether the abnormal levels of

alkaline phosphatase and osteocalcin in OA bone tissues were due to

inherent abnormalities in human OA osteoblasts or to an abnormal

response of the osteoblasts to regulatory signals. Using bone samples

from OA patients undergoing joint-replacement surgery, they found that

the OA osteoblasts responded normally to hormonal stimulation but had an

underlying " striking increase in osteocalcin production, " increased

levels of IGF-1, and reduced sensitivity to PTH compared with

osteoblasts from non-OA subjects.

" OA subchondral osteoblasts have a normal 1,25(OH)2D3 [the active

metabolite of vitamin D3] response in vitro yet present elevated

alkaline phosphatase activity and elevated osteocalcin release. We also

found that OA osteoblasts have elevated osteocalcin messenger RNA [mRNA]

levels by Northern blot analysis with a normal 1,25(OH)2D3 response, ie,

1,25(OH)2D3 increases osteocalcin mRNA levels several-fold from near

zero under basal conditions, " Lajeunesse tells rheumawire. " IGF-1 is one

of the most potent stimulators of osteoblasts, yet it is also regulated

locally by IGF binding proteins. Increasing IGF-1 locally may stimulate

cell growth and could also contribute to collagen production. "

Resistance to PTH regulation may be due to a decrease in PTH-receptor

numbers. Lajeunesse found that decreases in the levels of mRNA for PTH

receptors in osteoblasts paralleled OA severity, with patients whose OA

was moderate retaining greater PTH sensitivity than those with severe

OA. Blocking IGF-1 signaling with anti-IGF-1 antibodies increased

PTH-receptor mRNA levels, while adding IGF-1 decreased PTH-receptor

levels in the OA osteoblasts.

Elevated endogenous production of prostaglandin E2 (PGE2) and IGF-1 may

also contribute to reduced cyclic AMP (cAMP) production in response to

PTH. Lajeunesse found that OA osteoblasts produce 2 to 3 times the

normal amount of PGE2 and that using naproxen to block endogenous PGE2

production restores PTH-stimulated cAMP levels to normal.

" An increase in PGE2 could have multiple effects on bone cells depending

on its actual local concentration, " Lajeunesse says. " It can stimulate

osteoblasts, but at higher levels it could stimulate and/or recruit new

osteoclasts. "

OA patients could be divided into a " normal " category or a high PGE2

category based on in vitro production by osteoblasts, but these

categories did not correspond to clinical differences such as disease

duration, gross morphological and histological status, extent of

cartilage damage and loss, or severity of synovial inflammation.

" What is most important for the future would be to understand why

collagen deposition is so high in OA bone tissue, ie, the mechanisms

that trigger this increase, " Lajeunesse says.

Janis

Source

1. Lajeunesse D. The role of bone in the treatment of osteoarthritis(1).

Osteoarthritis Cartilage 2004; 12 Suppl A:34-8.