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© The Rockefeller University Press, 0021-9525/2002/9/1133 $5.00
The Journal of Cell Biology, Volume 158, Number 6, September 16, 2002 1133-1144

Hyaluronan–CD44 interaction hampers migration of osteoclast-like cells by down-regulating MMP-9

¹ Divisione di Oncologia Sperimentale 2, CRO-IRCCS, National Cancer Institute, 33081 Aviano, Italy
² Nucleo di Ricerca Clinica e Laboratoristica in Ematologia, CRO-IRCCS, National Cancer Institute, 33081 Aviano, Italy
³ Dipartimento di Biologia Evolutiva Funzionale, University of Parma, 43100 Parma, Italy
⁴ Dipartimento di Scienze e Tecnologie Biomediche, University of Udine, 33100 Udine, Italy
⁵ MATI Center of Excellence, University of Udine, 33100 Udine, Italy

Address correspondence to Alfonso Colombatti, Divisione di Oncologia Sperimentale 2 CRO-IRCCS, National Cancer Institute, 33081 Aviano, Italy. Tel.: 39-0434-659-365. Fax: 39-0434-659-428. E-mail: acolombatti{at}cro.it

Osteoclast (OC) precursors migrate to putative sites of bone resorption to form functionally active, multinucleated cells. The preOC FLG 29.1 cells, known to be capable of irreversibly differentiating into multinucleated OC-like cells, displayed several features of primary OCs, including expression of specific integrins and the hyaluronan (HA) receptor CD44. OC-like FLG 29.1 cells adhered to and extensively migrated through membranes coated with fibronectin, vitronectin, and laminins, but, although strongly binding to HA, totally failed to move on this substrate. Moreover, soluble HA strongly inhibited OC-like FLG 29.1 cell migration on the permissive matrix substrates, and this behavior was dependent on its engagement with CD44, as it was fully restored by function-blocking anti-CD44 antibodies. HA did not modulate the cell–substrate binding affinity/avidity nor the expression levels of the corresponding integrins. MMP-9 was the major secreted metalloproteinase used by OC-like FLG 29.1 cells for migration, because this process was strongly inhibited by both TIMP-1 and GM6001, as well as by MMP-9–specific antisense oligonucleotides. After HA binding to CD44, a strong down-regulation of MMP-9 mRNA and protein was detected. These findings highlight a novel role of the HA–CD44 interaction in the context of OC-like cell motility, suggesting that it may act as a stop signal for bone-resorbing cells.

Key Words: bone; cell migration; hyaluronic acid; metalloproteinase; osteoclast

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