Trabecular Bone Deterioration in col9a1+/− Mice Associated With Enlarged Osteoclasts Adhered to Collagen IX–Deficient Bone

Abstract

ABSTRACT: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 CT and nondecalcified histology. Osteoblastic and osteoclastic activities were evaluated by PCR-and microarraybased 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.

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

“…In the Atlantic salmon, COL11A2 is expressed throughout the notochord in early stages of development, but quickly becomes confined to the segmented, non-mineralizing regions of the notochord, suggesting a similar role for COL11A2 in inhibiting mineralization [87]. COL9A1 may have a role in postnatal bone maintenance, as COL9A1 +/− and −/− mice develop osteoporosis in association with an increased osteoclast number and activity in trabecular bone [88]. Additionally, mutations in COL9A1 , COL9A2 , and COL9A3 may cause multiple epiphyseal dysplasia, which is characterized by abnormal ossification of the epiphyses [89].…”

Molecular breakpoint mapping of 6q11‐q14 interstitial deletions in seven patients

“…However, a mouse model with collagen IX deficiency (Col9a1À/Àmice) showed compromised development [Dreier et al, 2008] and maturation [Opolka et al, 2007] of cartilage. Haploinsufficiency of collagen IX (Col9a1þ/Àmice) caused abnormally flattened and enlarged osteoclasts, potentially impairing catabolic bone remodelling [Wang et al, 2008]. Although lack of type IX collagen is associated with early onset osteoarthritis [Fassler et al, 1994], increased severity of arthritis [Carlsen et al, 2006], and multiple epiphyseal dysplasia [Czarny-Ratajczak et al, 2001], our patients have not as yet developed cartilage disorders.…”

Genetic Networks in Osseointegration

“…Type X collagen may increase the tensile strength of interface tissues such as peri-implant bone. In addition, a study on Col9 knockout bone showed significantly increased susceptibility to osteoclastic bone resorption (Wang et al, 2008). The long-term resistance of peri-implant bone against catabolic remodeling might be contributed, in part, by its unique ECM composition.…”