what-when-how
In Depth Tutorials and Information
Shared Heritability and Genetic Factors
Several authors have studied the genetic susceptibility
of OA and a number of candidate genes have been impli-
cated in the pathogenesis of OA.
6-8
These include single
nucleotide polymorphisms (SNPs) in certain genes that
have a known role in skeletal development such as trans-
forming growth factor beta (TGF-β) and bone morphoge-
netic protein (BMP) as well as genes in the Wnt signaling
pathway.
9
The earliest sign of OA is cellular proliferation
and remodeling as outlined below in detail in the sec-
tion “Alterations in the Rate of Bone Turnover.” Articular
chondrocytes synthesize pro-inflammatory cytokines
such as interleukin (IL)-1, IL-1β, IL-17, IL-18 and TNF-
α.
9-11
Tissue destructive enzymes such as matrix metal-
loproteases (MMPs), cathepsin K and ADMATS (a
disintegrin and metalloproteinase with thrombospondin
motifs) have also been implicated in the progression of
OA at the molecular level.
The cells also express molecules which are associated
with chondrocyte hypertrophy (collagen type X) and
terminal differentiation such as vascular endothelial
growth factor (VEGF), runt-related transcription factor
2 (RUNX 2) and MMP-13. Chondrocyte hypertrophy
leads to increased calcified cartilage and new bone for-
mation as outlined below.
Modeling, on the other hand, is the process where
bone resorption and bone formation occur without
coupling, but it contributes to alteration in the struc-
ture and function of subchondral and trabecular
bone. Osteophyte formation is another hallmark of
OA pathogenesis. This is a consequence of reactiva-
tion of endochondral ossification at the joint margins.
Several studies have demonstrated that one of the earli-
est changes that occurs in the joint prior to clinical and
radiographic evidence of OA is increased penetration
of the zone of calcified cartilage by vascular elements.
14
Increased local growth factors and pro-angiogenic fac-
tors, such as TGF-β and BMP-2 have been implicated in
the process. This leads to chondrocyte hypertrophy and
increased calcified cartilage and new bone formation.
This causes the duplication of the tidemark (
Figure 38.1
)
and the calcified cartilage advances deep into the articu-
lar cartilage. The consequence of this process is thinning
of the articular cartilage zone and altered biomechanical
properties of the joint.
15
Several studies have looked at early skeletal changes
in OA and have concluded that changes in bone turn-
over precede radiographic OA and also predict the sub-
sequent development of osteophytes and subchondral
bone sclerosis.
Structural Alterations in the Subchondral Bone
Subchondral bone is known to be the shock absorber
in a normal joint and it also provides support as well
as nutrients to the cartilage. As outlined above during
the pathogenesis of OA, there is increased bone turn-
over and there is duplication of the tidemark as well as
increased angiogenesis and ultimately an increase in the
subchondral bone thickness. This new thickened sub-
chondral bone is stiff and less elastic and consequently
has less capacity to absorb shock. As a result, there is
increased load on the overlying cartilage, which in turn
Alterations in the Rate of Bone Turnover
In normal joints, the articular cartilage is separated
from the subchondral bone by calcified cartilage. The area
separating the hyaline articular cartilage and the calci-
ied cartilage is usually referred to as the tidemark.
12
The
subchondral bone consists of non-porous, poorly vas-
cularized cortical bone and trabecular bone. During the
pathogenesis of OA, both the cortical and trabecular bone
are modified by several mechanisms. There are micro-
cracks in the structure of the bone which independently
affect the ability of the bone to adapt to mechanical forces
and applied load. Additionally, the bone architecture is
modified due to bone turnover. The primary processes
involved in this alteration are bone remodeling and mod-
eling and endochondral ossification.12,13
12,13
During the process of bone remodeling, there is ini-
tially a period of bone resorption mediated by osteo-
clasts followed by a period of bone formation mediated
by osteoblasts. These activities in a physiologic state are
“coupled” whereby the bone mass is maintained. This
mechanism provides a way for the skeleton to adapt to
changing mechanical forces such as loading. Various
authors have shown that, during the pathogenesis of
OA, significant changes occur in the rate and extent of
remodeling in the subchondral bone which may affect
the state of mineralization and impair the capacity of
the bone to deform under load.
Articular
cartilage
Tidemark
Duplication
Subchondral
cortical bone
FIGURE 38.1
Histologic features associated with advanced osteo-
arthritis. There is fragmentation and fissuring of the articular carti-
lage. Also, there is duplication of the tidemark with advancement of
the calcified cartilage into the lower zones of the articular cartilage
further contributing to thinning of the cartilage lining.
(Courtesy of Edward DiCarlo, MD, Hospital for Special Surgery, New
York, NY.
Reproduced
with permission from Ther Adv Musculoskelet Dis.
2012.)
