Chondromodulin I Is a Bone Remodeling Factor

Chondromodulin I (ChM-I) was supposed from its limited expression in cartilage and its functions in cultured chondrocytes as a major regulator in cartilage development. Here, we generated mice deficient in ChM-I by targeted disruption of the ChM-I gene. No overt abnormality was detected in endochondral bone formation during embryogenesis and cartilage development during growth stages of ChM-I / mice. However, a significant increase in bone mineral density with lowered bone resorption with respect to formation was unexpectedly found in adult ChM-I / mice. Thus, the present study established that ChM-I is a bone remodeling factor. Endochondral bone development during embryogenesis and longitudinal bone growth in growing vertebrates require continuous cartilage growth (18). Proliferating chondrocytes originate from a region of resting chondrocytes, differentiate first into prehypertrophic chondrocytes and then into hypertrophic chondrocytes able to secrete the cartilage matrix. Through invasion by blood vessels, the calcified cartilage and vascular matrix are gradually replaced by bone matrix with the recruitment of osteoclasts and osteoblasts that mediate bone resorption and formation and eventual bone remodeling (1, 30). Thus, in bone growth, blood vessel invasion into cartilage is pivotal to the process of endochondral bone formation. Distinct classes of factors are thought to play cognate roles in the spatiotemporal regulation of the complicated yet sequential processes of cartilage differentiation and bone formation, particularly in angiogenic events. Fibroblast growth factor-2 (5, 31), transforming growth factor (3), and vascular endothelial growth factor (4) are expressed in cartilage and have been identified as strong angiogenic agents. However, these factors are also present in avascular cartilage and in surrounding vascular regions. These findings raise the possibility that the actions of angiogenic factors may be suppressed by the inhibitory action of a specific factor in avascular cartilage. While tissue inhibitors of matrix metalloproteinase 1 and 2 have been identified from cartilage as possible angiogenesis inhibitors, they are also expressed in other tissues (20). The search for a cartilage-specific inhibitor of angiogenesis led to the identification of chondromodulin I (ChM-I), initially isolated from bovine epiphyseal cartilage as a factor with growthpromoting activity on cultured chondrocytes (10). ChM-I was found to be a potent stimulator of proteoglycan synthesis in growth plate chondrocytes and of chondrocyte colony formation in agarose (12). However, ChM-I inhibited cultured vascular endothelial cell tube morphogenesis and growth (8, 9). Thus, the physiological significance of ChM-I during endochondral bone formation as a bifunctional factor of chondrocyte growth and angiogenesis inhibition was suggested from distinct lines of evidence in vitro (27). However, due to the lack of mice deficient in ChM-I, there has been no information regarding the physiological role of ChM-I. In the present study, we disrupted the murine ChM-I gene by homologous recombination to generate ChM-I knockout (ChM-I / ) mice. Homozygous ChM-I / mice were born without overt abnormalities and grew normally. Unexpectedly, ChM-I / mice exhibited no aberrations in endochondral bone formation during embryogenesis or in cartilage development during growth stages. However, a significant increase in bone mineral density was observed in 12-week-old ChM-I / mice. Analyses of bone formation and resorption indicators revealed that bone minerals accumulated in ChM-I / mice due to lowered bone resorption with respect to formation. Thus, our study revealed that the physiological role of ChM-I appears to be involved in the stimulation of bone remodeling through control of osteoclast and osteoblast functions rather than in cartilage development in intact animals.