Collagen VIα2 chain deficiency causes trabecular bone loss by potentially promoting osteoclast differentiation through enhanced TNFα signaling

Abstract

Type VI collagen is well known for its role in muscular disorders, however its function in bone is still not well understood. To examine its role in bone we analyzed femoral and vertebral bone mass by micro-computed tomography analysis, which showed lower bone volume/total volume and trabecular number in Col6α2-KO mice compared with WT. Dynamic histomorphometry showed no differences in trabecular bone formation between WT and Col6α2-KO mice based on the mineral appositional rate, bone formation rate, and mineralizing perimeter. Femoral sections were assessed for the abundance of Tartrate Resistant Acid Phosphatase-positive osteoclasts, which revealed that mutant mice had more osteoclasts compared with WT mice, indicating that the primary effect of Col6a2 deficiency is on osteoclastogenesis. When bone marrow stromal cells (BMSCs) from WT and Col6α2-KO mice were treated with rmTNFα protein, the Col6α2-KO cells expressed higher levels of TNFα mRNA compared with WT cells. This was accompanied by higher levels of p-p65, a downstream target of TNFα, suggesting that BMSCs from Col6α2-KO mice are highly sensitive to TNFα signaling. Taken together, our data imply that Col6a2 deficiency causes trabecular bone loss by enhancing osteoclast differentiation through enhanced TNFα signaling. Bone is a highly dynamic tissue that depends on specialized cell types to regulate its formation and structural integrity. Bones are formed by the anabolic actions of osteoblasts. Osteoblasts share a close relationship with catabolic osteoclasts that resorb or digest bones. The coupled actions of bone resorption and subsequent bone formation is known as "bone turnover", a process that replaces and renews bone tissue that has microdamage from impact or aging. An imbalance of bone turnover results in either osteopetrosis, which is excess bone matrix, or osteopenia, which is insufficient bone matrix. In both cases, the bone is fragile and prone to breakage. Identifying novel factors that affect the osteoblast-osteoclast relationship will improve our understanding of bone turnover and pave the way for future bone therapies. Osteogenic cells are surrounded by mineralized connective tissue composed of collagen fibrils and noncollagenous proteins. These matrix components serve as nucleation sites for depositing the carbonate-rich apatite that provides strength and stiffness to the bone. Type I collagen is the most abundant collagen in bone and is composed of two α1(I) and one α2(I) chains that are assembled into a triple helical structure. These helices further aggregate to form fibrils outside the cell. The importance of type I collagen in bone is clearly illustrated

Type VI Collagen Regulates Endochondral Ossification in the Temporomandibular Joint

“…Because type VI collagen is highly expressed in the ECM of the TMJ cartilage, we used a α2(VI)‐deficient ( Col6α2 ‐KO) mouse model that is unable to secrete any type VI collagen into its ECM ( 18 ) to determine its function during endochondral ossification. μCT was used to visualize the mineralized tissues in WT and Col6α2 ‐KO condyles at 1 month, 3 months, and 6 months of age (Fig.…”

“…(53,54) In addition, our previous study in long bones showed type VI collagen binds to Tnfα and works by harnessing its activity. (18) It is possible that type VI collagen directly binds to Bmp2 in the cartilage; however, additional biochemical experiments would need to be carried out to prove this point. Regarding the integrity of the ECM, we show here distinct changes in gene expression profiles related to ECM organization.…”

Coordinate roles for collagen VI and biglycan in regulating tendon collagen fibril structure and function

“…We elucidated the structural impact of loss of biglycan, collagen VI, or both molecules on collagen fibril architecture in mature tendons. The models used were global knockouts of biglycan ( Bgn -/0 ) and/or collagen VI ( Col6a2 -/- ), the latter of which results in a total loss of collagen VI trimer secretion [37] , [38] . TEM images of FDL tendon sections were analyzed from 2 month-old WT, Bgn -/0 , Col6a2 -/- , and Col6a2 -/- ;Bgn -/0 mice.…”

“…However, it is likely that the relative molecular presence of biglycan is much higher than that of collagen VI in healing tendons. To determine if this phenomena is specific to tendon, we examined relative mRNA ratios in age and gender matched WT bones and found Bgn mRNA is also 10x more abundant than that of Col6a1 , Col6a2, or Col6a3 [43] . The ramification of this observation is not clear and will require further investigation to fully understand its functional consequences.…”

Analysis of the cells isolated from epithelial cell rests of Malassez through single-cell limiting dilution

“…These include downregulation of BGN and COL6A2 and upregulation of EGFR and FLT-1 compared to CRUDE and ERM-3. BGN is an osteogenesis promoter gene, and COL6A2 is a negative regulator of osteoclastogenesis 40 , 41 . EGFR is an EGF receptor continually generated by ERM cells in the PDL region and aids in the maintenance of the human periodontal gap thickness between 0.20 and 0.40 mm.…”