**11. Role of IHH in Chondrogenesis**

Indian hedgehog (Ihh) [197], a member of the hedgehog protein family along with sonic hedgehog (Shh) [198], regulates chondrocyte differentiation, proliferation and maturation in articular cartilage development [199] and during endochondral ossification through interactions with parathyroid hormone-related peptide (PTHrP) [200] and BMP mediated cell signalling [201]. Ihh has multiple functions during skeletogenesis [202–204]. Mice lacking the Ihh gene exhibit severe skeletal abnormalities, including markedly reduced chondrocyte proliferation and abnormal maturation and an absence of mature osteoblasts, which has detrimental effects on bone development [205]. Ihh and its receptor, smoothened (smo), are expressed in chondrocytes and osteoblasts thus Ihh may have a direct effect on osteoblasts, or its effects may be mediated indirectly through chondrocytes during the process of endochondral ossification.

IHH colocalises with aggrecan in the growth plate (Figure 4A,B; plate A g; B c,f). Aggrecan regulates the expression of growth factors and signalling molecules during cartilage development and is essential for proper chondrocyte organisation, morphology and survival during formation of the axial skeleton. The sulphated GAGs of the CS and KS side chains of aggrecan provide water imbibing properties creating a large hydrophilic molecule important for the hydration of cartilage and the provision of its hydrodynamic weight-bearing properties but also bind growth factors and morphogens crucial to chondrocyte maturation and function [27,206]. Thus, aggrecan should not be considered merely as a space-filling ECM component that provides hydration and weight-bearing properties to tissues but also a cell directive tissue organiser that is capable of modulating the activity of growth factors and morphogenetic proteins, thus mediating tissue development. Indeed, aggrecan knock-out mutants display a range of severe ECM defects, which supports this proposal [134,165].
