Cyclin-dependent kinase 10 controls bone formation and is linked to human skeletal health
Yu, Daiyang ; Tanaka, Tomoyuki ; Miyakoshi, Yuri ; Kato, Tsuyoshi ; Ochi, Hiroki ; Sato, Shingo ; Yoshii, Toshitaka ; Al Kaissi, Ali ; Kaldis, Philipp LU
and Inose, Hiroyuki
(2026)
In Journal of Orthopaedic Translation
56.
- Abstract
BACKGROUND/OBJECTIVE: Bone remodeling is a critical process for skeletal health, and its dysregulation can lead to diseases like osteoporosis. While several Cyclin-Dependent Kinases (CDKs) are known to regulate bone metabolism, the function of CDK10 remains uncharacterized in this context. Human mutations in
CDK10 cause the Al Kaissi syndrome, which involves severe skeletal defects, suggesting a role for CDK10 in bone. The objective of this study was to investigate the functional role of CDK10 in bone remodeling in mice
in vivo.
METHODS: The
in vitro role of CDK10 was examined in the MC3T3-E1 osteoblast precursor cell line and primary osteoblasts using siRNA-mediated knockdown and plasmid-based... (More)BACKGROUND/OBJECTIVE: Bone remodeling is a critical process for skeletal health, and its dysregulation can lead to diseases like osteoporosis. While several Cyclin-Dependent Kinases (CDKs) are known to regulate bone metabolism, the function of CDK10 remains uncharacterized in this context. Human mutations in
CDK10 cause the Al Kaissi syndrome, which involves severe skeletal defects, suggesting a role for CDK10 in bone. The objective of this study was to investigate the functional role of CDK10 in bone remodeling in mice
in vivo.
METHODS: The
in vitro role of CDK10 was examined in the MC3T3-E1 osteoblast precursor cell line and primary osteoblasts using siRNA-mediated knockdown and plasmid-based overexpression. Cell proliferation and osteogenic differentiation were assessed. To investigate its
in vivo function, an osteoblast lineage-specific knockout mouse model (
Cdk10osb-/-) was generated by crossing
Osterix-Cre mice with
Cdk10flox/flox mice. Skeletal phenotypes were analyzed using micro-computed tomography (μCT) and histomorphometry. Cellular mechanisms were explored via Ki-67 (proliferation) and TUNEL (apoptosis) staining. Transcriptional changes were identified using RNA sequencing (RNA-seq) of bone tissue. Finally, bone mineral density was evaluated in a small cohort of human patients with
CDK10 mutations.
RESULTS: In vitro, both knockdown and overexpression of
Cdk10 paradoxically inhibited the proliferation of MC3T3-E1 cells and primary osteoblasts. In vivo,
Cdk10osb-/- mice developed an osteoporotic phenotype with reduced trabecular and cortical bone mass. Histomorphometry revealed that this was caused by impaired bone formation, characterized by a reduction in osteoblast number and surface, and a decreased bone formation rate. Osteoclast parameters remained unchanged. The decrease in osteoblasts was attributed to reduced proliferation (fewer Ki-67 positive cells), not increased apoptosis. RNA-seq of
Cdk10osb-/- bone identified downregulation of Bglap (Osteocalcin), a key osteoblast marker. Consistent with these findings, human patients with
CDK10 mutations were found to have low bone mineral density (osteopenia).
CONCLUSION: Our study establishes CDK10 as an essential regulator of osteoblast proliferation and bone formation
in vivo. Its deficiency leads to osteoporosis, mirroring human skeletal pathology and highlighting CDK10 as a critical factor in maintaining skeletal integrity.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This research establishes Cyclin-Dependent Kinase 10 (CDK10) as a critical regulator of bone formation. Mouse studies demonstrate that osteoblast-specific Cdk10 deletion causes osteoporosis, mirroring osteopenia in humans with CDK10 mutations. These findings highlight CDK10 as a potential diagnostic marker and a novel therapeutic target for skeletal disorders characterized by impaired bone formation, such as osteoporosis.
(Less)
- author
- Yu, Daiyang
; Tanaka, Tomoyuki
; Miyakoshi, Yuri
; Kato, Tsuyoshi
; Ochi, Hiroki
; Sato, Shingo
; Yoshii, Toshitaka
; Al Kaissi, Ali
; Kaldis, Philipp
LU
and Inose, Hiroyuki
- organization
- publishing date
- 2026-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Orthopaedic Translation
- volume
- 56
- article number
- 101018
- publisher
- Elsevier
- external identifiers
-
- pmid:41836559
- scopus:105032201161
- ISSN
- 2214-031X
- DOI
- 10.1016/j.jot.2025.10.010
- language
- English
- LU publication?
- yes
- id
- ae844fcd-9357-4e0e-ac0b-466d8259adbe
- date added to LUP
- 2026-03-20 09:52:12
- date last changed
- 2026-05-30 11:32:15
@article{ae844fcd-9357-4e0e-ac0b-466d8259adbe,
abstract = {{<p>BACKGROUND/OBJECTIVE: Bone remodeling is a critical process for skeletal health, and its dysregulation can lead to diseases like osteoporosis. While several Cyclin-Dependent Kinases (CDKs) are known to regulate bone metabolism, the function of CDK10 remains uncharacterized in this context. Human mutations in <br>
CDK10 cause the Al Kaissi syndrome, which involves severe skeletal defects, suggesting a role for CDK10 in bone. The objective of this study was to investigate the functional role of CDK10 in bone remodeling in mice <br>
in vivo.<br>
</p><p>METHODS: The <br>
in vitro role of CDK10 was examined in the MC3T3-E1 osteoblast precursor cell line and primary osteoblasts using siRNA-mediated knockdown and plasmid-based overexpression. Cell proliferation and osteogenic differentiation were assessed. To investigate its <br>
in vivo function, an osteoblast lineage-specific knockout mouse model (<br>
Cdk10osb-/-) was generated by crossing <br>
Osterix-Cre mice with <br>
Cdk10flox/flox mice. Skeletal phenotypes were analyzed using micro-computed tomography (μCT) and histomorphometry. Cellular mechanisms were explored via Ki-67 (proliferation) and TUNEL (apoptosis) staining. Transcriptional changes were identified using RNA sequencing (RNA-seq) of bone tissue. Finally, bone mineral density was evaluated in a small cohort of human patients with<br>
CDK10 mutations.<br>
</p><p>RESULTS: In vitro, both knockdown and overexpression of <br>
Cdk10 paradoxically inhibited the proliferation of MC3T3-E1 cells and primary osteoblasts. In vivo, <br>
Cdk10osb-/- mice developed an osteoporotic phenotype with reduced trabecular and cortical bone mass. Histomorphometry revealed that this was caused by impaired bone formation, characterized by a reduction in osteoblast number and surface, and a decreased bone formation rate. Osteoclast parameters remained unchanged. The decrease in osteoblasts was attributed to reduced proliferation (fewer Ki-67 positive cells), not increased apoptosis. RNA-seq of<br>
Cdk10osb-/- bone identified downregulation of Bglap (Osteocalcin), a key osteoblast marker. Consistent with these findings, human patients with <br>
CDK10 mutations were found to have low bone mineral density (osteopenia).<br>
</p><p>CONCLUSION: Our study establishes CDK10 as an essential regulator of osteoblast proliferation and bone formation <br>
in vivo. Its deficiency leads to osteoporosis, mirroring human skeletal pathology and highlighting CDK10 as a critical factor in maintaining skeletal integrity.<br>
</p><p>THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This research establishes Cyclin-Dependent Kinase 10 (CDK10) as a critical regulator of bone formation. Mouse studies demonstrate that osteoblast-specific Cdk10 deletion causes osteoporosis, mirroring osteopenia in humans with CDK10 mutations. These findings highlight CDK10 as a potential diagnostic marker and a novel therapeutic target for skeletal disorders characterized by impaired bone formation, such as osteoporosis.</p>}},
author = {{Yu, Daiyang and Tanaka, Tomoyuki and Miyakoshi, Yuri and Kato, Tsuyoshi and Ochi, Hiroki and Sato, Shingo and Yoshii, Toshitaka and Al Kaissi, Ali and Kaldis, Philipp and Inose, Hiroyuki}},
issn = {{2214-031X}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Journal of Orthopaedic Translation}},
title = {{Cyclin-dependent kinase 10 controls bone formation and is linked to human skeletal health}},
url = {{http://dx.doi.org/10.1016/j.jot.2025.10.010}},
doi = {{10.1016/j.jot.2025.10.010}},
volume = {{56}},
year = {{2026}},
}