Trabecular bone deterioration in col9a1+/- mice associated with enlarged osteoclasts adhered to collagen IX-deficient bone

Jake Wang Chiachien, Keisuke Iida, Hiroshi Egusa, Akishige Hokugo, Anahid Jewett, Ichiro Nishimura

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


Introduction: Short collagen IX, the exclusive isoform expressed by osteoblasts, is synthesized through alternative transcription of the col9a1 gene. The function of short collagen IX in bone was characterized in col9a1-null mutant mice. Materials and Methods: Trabecular bone morphometry of lumbar bones and tibias was evaluated by μCT and nondecalcified histology. Osteoblastic and osteoclastic activities were evaluated by PCR- and microarray-based gene expression assays and TRACP-5b and C-terminal telopeptide (CTX) assays, as well as in vitro using bone marrow stromal cells and splenocytes. The effect of col9a1+/- mutation on osteoclast morphology was evaluated using RAW264.7-derived osteoclastic cells cultured on the mutant or wildtype calvarial bone substrates. Results: Col9a1 knockout mutation caused little effects on the skeletal development; however, young adult female col9a1-/- and col9a1+/- mice exhibited significant loss of trabecular bone. The trabecular bone architecture was progressively deteriorated in both male and female heterozygous col9a1+/- mice while aging. The aged mutant mice also exhibited signs of thoracic kyphosis and weight loss, resembling the clinical signs of osteoporosis. The col9a1+/- osteoblasts synthesized short col9a1 transcripts at decreased rates. Whereas bone formation activities in vitro and in vivo were not affected, the mutant osteoblast expressed the elevated ratio of RANKL/osteoprotegerin. Increased serum TRACP-5b and CTX levels were found in col9a1+/- mice, whose bone surface was associated with osteoclastic cells that were abnormally flattened and enlarged. The mutant and wildtype splenocytes underwent similar osteoclastogenesis in vitro; however, RAW264.7-derived osteoclastic cells, when cultured on the col9a1+/- calvaria, widely spread over the bone surface and formed large resorption pits. The surface of col9a1+/- calvaria was found to lack the typical nanotopography. Conclusions: The mineralized bone matrix deficient of short collagen IX may become susceptible to osteoclastic bone resorption, possibly through a novel non-cell-autonomous mechanism. The data suggest the involvement of bone collagen IX in the pathogenesis of osteoporosis.

Original languageEnglish
Pages (from-to)837-849
Number of pages13
JournalJournal of Bone and Mineral Research
Issue number6
Publication statusPublished - 2008 Jun


  • Collagen IX
  • Osteoclast
  • Osteoporosis
  • Rodent
  • μCT bone morphometry


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