Table 1

Different signaling factors involved in both chondrocyte differentiation processes during endochondral ossification and in osteoarthritis

Signaling factor

Effects on growth plate chondrocytes

Role in OA


Bone morphogenic proteins

Induce proliferation

Stimulation of MMP-13

Inhibit hypertrophy

Fibroblast growth factors

Decrease proliferation

Stimulation of ADAMTS-5

Decrease hypertrophy

Decrease matrix production

TGFβ

Variable effects depending on species and concentration

Stimulation of MMP-13

Wnt/β-catenin

Positive regulator of hypertrophy and ossification

Activation of maturational genes

Induction of matrix degradation

Induction of MMPs and aggrecanases mediated by WISP-1

Indian hedgehog

Stimulates proliferation

Induction of ADAMTS-5 via Runx2

Inhibits hypertrophy via parathyroid hormone-related peptide

Directly induces hypertrophy in vitro

Retinoic acid

Positive regulator of hypertrophy and matrix mineralization

Induction of MMP-13 and aggrecanases

Growth hormone/IGF-I

Stimulate proliferation

Growth hormone is a beneficial factor in OA

Initiate hypertrophy

IGF-I signaling is antagonized by IGF-binding proteins

Collagen IX

Stimulates chondrocyte proliferation

Essential for tissue integrity, loss of collagen IX induces OA

Essential for columnar organization of growth plate chondrocytes

β1 integrins

Mediate adhesion to surrounding matrix and motility

Essential for normal knee joint development

Essential for proliferation

Minor influence on cartilage homeostasis

Discoidin domain receptors

Regulate cell proliferation, adhesion and motility

Induction of MMP-13 and MMP-derived type II collagen

Fragments

Control matrix remodeling

MMPs/ADAMTSs

Essential for matrix remodeling

Key factors in matrix degradation during OA

Influence bioavailability of VEGF

Matrix degradation is accompanied by terminal

chondrocyte differentiation, positive feedback

mechanism?

Sox 9

Regulate proliferation and hypertrophic differentiation

Involved in MMP-13 expression

Runx2/3

Positive regulation of chondrocyte hypertrophy

Induction of chondrocyte hypertrophy

Influence on angiogenesis by up regulation of VEGF

Induction of MMP-13 expression

CCAAT/enhancer binding

Inhibition of proliferation

Mediates cartilage destruction protein beta

Stimulation of hypertrophy

Activation of collagen X expression


Note that cartilage degradation in osteoarthritis (OA) is mediated by matrix metalloproteinase (MMP)-13 and aggrecanases (a disintegrin and metalloprotease with trombospondine motifs (ADAMTS)-4 and ADAMTS-5) expressed by hypertrophic chondrocytes. See relevant references in the text. IGF, insulin-like growth factor; TGFβ, transforming growth factor beta; VEGF, vascular endothelial growth factor.

Dreier Arthritis Research & Therapy 2010 12:216   doi:10.1186/ar3117