TABLE 1.
Summary of phenotypes of genome‐editing mouse models in cartilage circadian clock disruption. Description of mouse models in the foetus, adolescence and adult stage in terms of alterations of body height/weight, cartilage/growth plate and bone compared with age‐matched wide‐type mice
| References | Mice | Detection of the Δallele | Age | General | Location | Visual observation and pathological | Protein | |
|---|---|---|---|---|---|---|---|---|
| Cartilage tissue/growth plate | Bone and other tissues | Cartilage tissue | ||||||
| Foetus stage | ||||||||
| Yu, et al35 | Bmal1 −/− | Exon 5 and part of exon 4 | E14.5‐18.5 | Body size decreased | Mandibular condyle | Chondrogenesis decreased | Alizarin red staining decreased | COL2A1, COL10A1, ACAN, SOX9, CyclinD1 and Ki67 decreased; TUNEL‐positive cells increased |
| Bmal1fl/fl; Twist2‐Cre | ||||||||
| Ma, et al36 | TamCart Bmal1fl/fl | Not mentioned | E13.5‐18.5 | No abnormal | ||||
| Adolescence stage | ||||||||
| Bunger,MK., et al 46 | Bmal1 −/− | Exon 5 and part of exon 4 | W6‐11 | No abnormal | ||||
| Yu, et al 35 | Bmal1 −/− | Exon 5 and part of exon 4 | W4‐20 | —— | Mandibular condyle | Shorter PZ and HZ; number of chondrocytes per column in PZ and HZ decreased | BMD, BV/TV, Tb. Th and Tb.N decreased; Tb. Sp increased | COL2A1, ACAN, COL10A1 and Ki67 decreased; TUNEL‐positive cells increased |
| Suyama,K., et al 47 | Bmal1 −/− | Exon 5 and part of exon 4 | W10 | —— | Lumbar spine | Disc height and DHI decreased; lower matrix‐to‐cell ratio in NP; hyperplasia in AF | Vertebral bone BV, TV, BV/TV, Tb.N and Tb. Th decreased; Tb. Sp increased | —— |
| Ma, et al 36 | TamCart Bmal1fl/fl | Not mentioned | W4‐6 | Body weight and length decreased | Hindlimb | Shorter PZ; larger HZ | Shorter | BrdU‐positive cells, COL10A1, VEGF, HIF1α, and Bcl‐2 decreased; TUNEL‐positive cells, Caspase‐3, MMP13 and Runx2 increased |
| Dudek, et al 44 | Col2α1‐Bmal1 −/− | Exon 8 | W4‐12 | No abnormal | Knee joint | Cell apoptosis near the tidemark; loss of chondrocytes and voids in ECM | No abnormal | —— |
| Takarada, et al 45 | Bmal1 −/− | Exon 6‐8 | W3‐15 | Body length/weight decreased | Rib | —— | —— | IHH decreased; no abnormal with Col II, Col X, Sox9, Runx2 |
| α1(II)‐collagen‐Cre; Bmal1fl/fl | Hindlimb | —— | Shorter | IHH decreased | ||||
| Adult stage | ||||||||
| Bunger, et al46 | Bmal1 −/− | Exon 5 and part of exon 4 | W20‐40 | Body weight decreased; abnormal gait and posture | Tarsal joint | —— | Calcified nodules; calcaneal tendon calcification; osteocalcin increased; no abnormal in BMD | —— |
| Vertebrae | Proliferative bone bridging from the costal cartilage to the sternum; increased matrix deposition and bone proliferation in perichondrium | Bridging ankylosis and osteophyte in intervertebral and lumbar joints; no abnormal in BMD | —— | |||||
| Knee joint | No abnormal | Tendons and ligaments ectopic calcification/ossification; no abnormal in BMD | —— | |||||
| Schroder, et al 54 | Bmal1 −/− | Exon 8 | W20‐22 | —— | Hindlimb and Ribcage | Alcian Blue decreased | Distal tibia thicker; calcification of the calcaneal tendon | —— |
| iMS‐Bmal1 −/− | W75‐79 | Hair loss; dermatitis increased; kyphosis | ||||||
| Dudek, et al52 | Col2α1‐Bmal1 −/− | Exon 8 | W24‐48 | —— | Intervertebral disc | Thinner; gradual disappearance of CEP; bone bridges; fibrosis | Ectopic ossification | Adamts1, Adamts5, Adamts15 and Follistatin increased |
| Hand, et al56 | Col6α1‐Bmal1 −/− | Exon 8 | W12‐36 | —— | Ankle joint | —— | Density increased; calcaneal spur; calcification between the metatarsal and phalangeal bones; chondroid metaplasia at the junction of the synovium, joint capsule and enthesis repair tissue | —— |
| Intervertebral disc | Calcification | —— | —— | |||||
| Yuan, et al 58 | ClockΔ19 | Exon 19 | W24 | Knee joint | —— | Safranin‐O staining decreased; cartilage and meniscus damage histologic scores increased | —— | —— |
| Kc, et al 11 | ClockΔ19/Δ19 | Exon 19 | W7‐9 | Knee, shoulder, spine disc and facet joints | No abnormal | |||
PZ: Proliferative zone; HZ: Hypertrophic zone; BMD: Bone mineral density; BV/TV: bone volume/total volume; Tb.Th: Trabecular thickness; Tb.N: Trabecular number; Tb.Sp: Trabecular separation; CEP: Cartilaginous end plate; IVD: Intervertebral disc; DHI: Disc height index; NP: Nucleus pulposus; AF: Annulus fibrosus; ECM: Extracellular matrix.